Coverage Policy Manual
Policy #: 2022001
Category: Pharmacy
Initiated: January 2022
Last Review: January 2024
  Efgartigimod (e.g., Vyvgart) and Efgartigimod alfa and Hyaluronidase-qvfc (e.g., Vyvgart Hytrulo)
Description:
Myasthenia gravis is a chronic autoimmune neuromuscular disease characterized by fluctuating weakness of the voluntary muscle groups. Common symptoms include weakness of the muscles that control the eyes, eyelids, facial expressions, chewing, talking, and swallowing. This condition is usually due to the presence of antibodies against acetylcholine receptors in the neuromuscular junction.
 
Efgartigimod binds to neonatal Fc receptor (FcRn) and stops it from recycling antibodies back into the blood. The process reduces the circulation of AChR antibodies, which are responsible for interfering with nerve-muscle communication in people with myasthenia gravis.
 
Regulatory Status
 
On December 17, 2021, the FDA approved efgartigimod (e.g., Vyvgart) for the treatment of generalized myasthenia gravis (gMG) in adult individuals who are anti-acetylcholine receptor (AChR) antibody positive.
 
On June 20, 2023, the FDA approved efgartigimod alfa and hyaluronidase-qvfc (e.g., Vyvgart Hytrulo) for the treatment of generalized myasthenia gravis (gMG) in adult individuals who are anti-acetylcholine receptor (AChR) antibody positive.
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
Prior Approval is required for efgartigimod (e.g., Vyvgart).
 
Prior Approval is required for efgartigimod alfa and hyaluronidase-gvfc (e.g., Vyvgart Hytrulo).
 
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, Tyson, 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 April 3, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Efgartigimod and efgartigimod and hyaluronidase 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:
 
INITIAL APPROVAL for up to 12 months:
 
1. Individual is 18 years of age or older (Vyvgart, 2024); AND
2. Individual has a diagnosis of generalized Myasthenia Gravis (gMG)  with Class II-IV disease per the Myasthenia Gravis Foundation of America (MGFA) classification system (see policy guidelines); AND
3. Individual has impaired activities of daily living defined as a Myasthenia Gravis-Specific Activities of Daily Living (MG-ADL) scale total score greater than or equal to 5 at initiation (see policy guidelines); AND
4. Individual is anti-AChR antibody positive (Vyvgart, 2024); AND
5. Individual has inadequate treatment response, intolerance, or contraindication to an acetylcholinesterase inhibitor (e.g., pyridostigmine) (Bird, 2024); AND
6. Individual meets one of the following:
a. Individual has inadequate treatment response to one or more of the following (Bird, 2024):
i. Azathioprine, 12-month trial; OR
ii. Cyclosporine, 7-month trial; OR
iii. Mycophenolate mofetil, 12-month trial; OR
iv. Tacrolimus, 12-month trial; OR
v. Glucocorticoids, 6-month trial; OR
vi. Methotrexate, 12-month trial; OR
vii. Cyclophosphamide, 3-month trial; OR
b. Individual has a documented intolerance or contraindication to all listed immunosuppressive therapies (e.g., azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, glucocorticoids, methotrexate or cyclophosphamide); OR
c. Individual is on a stable dose of one or more immunosuppressive therapies (e.g., azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, glucocorticoids, methotrexate or cyclophosphamide) and has required four or more rescue or bridge therapies [e.g., intravenous immune globulin (IVIG) or therapeutic plasma exchange] within 12 months (Alhaidar, 2022); AND
7. Individual will not be receiving concurrent chronic IVIG (does not include IVIG administered as rescue therapy) or other gMG biologic agent (e.g., eculizumab, ravulizumab, rituximab, inebilizumab, satralizumab, rozanolixizumab-noli) in combination with efgartigimob; AND
8. Must be prescribed by or in consultation with a neurologist with specialization in the treatment of gMG with Class II-IV disease; AND
9. Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for up to 12 months:
 
1. Individual continues to meet the initial treatment criteria; AND
2. Individual has experienced a decrease of 2 points in MG-ADL total score from pre-treatment baseline value; AND
3. Individual will not be receiving concurrent chronic IVIG (does not include IVIG administered as rescue therapy) or other gMG biologic agent (e.g., eculizumab, ravulizumab, rituximab, inebilizumab, satralizumab, rozanolixizumab-noli) in combination with efgartigimob; AND
4. Must be dosed in accordance with the FDA label.
 
Policy Guidelines
 
Myasthenia Gravis Foundation of America (MGFA) Clinical Classification:
 
    • Class I: any ocular weakness; all other muscle strength is normal
    • Class II: mild weakness affecting other than ocular muscles; may also have ocular weakness at any level
    • Class III: moderate weakness affecting other than ocular muscles; may also have ocular weakness at any level
    • Class IV: severe weakness affecting other than ocular muscles; may also have ocular weakness at any level
    • Class V: defined by intubation, with or without mechanical ventilation (Use of feeding tube without intubation = Class IVb)
 
Myasthenia Gravis Activities of Daily Living Scale (MG-ADL):
The MG-ADL scale assesses the impact of gMG on daily functions of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale; a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function. A total score ranges from 0 to 24, with the higher scores indicating more impairment. Score grade items are as follows (Wolfe, 1999):
 
Talking
    • 0 normal
    • 1 intermittent slurring or nasal speech
    • 2 constant slurring or nasal, but can be understood
    • 3 difficult to understand speech
Chewing
    • 0 normal
    • 1 fatigue with solid food
    • 2 fatigue with soft food
    • 3 gastric tube
Swallowing
    • 0 normal
    • 1 rare episode of choking
    • 2 frequent choking, necessitating changes in diet
    • 3 gastric tube
Breathing
    • 0 normal
    • 1 shortness of breath with exertion
    • 2 shortness of breath at rest
    • 3 ventilator dependence
Impairment of ability to brush teeth or comb hair
    • 0 none
    • 1 extra effort, but no rest periods needed
    • 2 rest periods needed
    • 3 cannot do one of these function
Impairment of ability to arise from a chair
    • 0 none
    • 1 mild, sometimes uses arms
    • 2 moderate, always uses arms
    • 3 severe, requires assistance
Double vision
    • 0 None
    • 1 occurs, but not daily
    • 2 daily, but not constant
    • 3 constant
Eyelid droop
    • 0 none
    • 1 occurs, but not daily
    • 2 daily, but not constant
    • 3 constant
 
Dosage and Administration
Dosing per FDA Guidelines
 
Efgartigimod (e.g., Vyvgart)
    • The recommended dosage for efgartigimod is 10 mg/kg administered as an intravenous infusion over one hour once weekly for 4 weeks. In individuals weighing 120 kg or more, the recommended dose is 1200 mg (3 vials) per infusion.
    • Administer subsequent treatment cycles based on clinical evaluation. The safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established.
    • If a scheduled infusion is missed, Efgartigimod may be administered up to 3 days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed.
    • Intravenous efgartigimod comes in a single dose vial of 400 mg/20 mL (20mg/mL) and should be administered by a healthcare professional.
 
Efgartigimod alfa and hyaluronidase-qvfc (e.g., Vyvgart Hytrulo)
    • The recommended dosage for efgartigimod alfa and hyaluronidase-gvfc 1,008 mg/11,200 units (1,008 mg efgartigimod alfa and 11,200 units hyaluronidase) administered subcutaneously over approximately 30 to 90 seconds in cycles of once weekly injections for 4 weeks.
    • Administer subsequent treatment cycles based on clinical evaluation; the safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established.
    • Efgartigimod alfa and hyaluronidase-gvfc is available as 1,008 mg efgartigimod alfa and 11,200 units hyaluronidase per 5.6 mL (180 mg/2,000 units per mL) in a single-dose vial.
 
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
 
Efgartigimod and efgartigimod and hyaluronidase, 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, efgartigimod and efgartigimod and hyaluronidase 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 October 2023 to April 2, 2024
 
INITIAL APPROVAL for up to 12 months:
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Efgartigimod and efgartigimod and hyaluronidase in the treatment of refractory generalized myasthenia gravis (gMG) 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:
 
1. Individual is 18 years of age or older (FDA, 2021); AND  
2. A diagnosis of refractory chronic generalized Myasthenia Gravis is confirmed by a neurologist with specialization in the treatment of myasthenia gravis with Class II-IV disease (per *MGFA criteria); AND
3. The individual has a myasthenia Gravis-Specific Activities of Daily Living scale (**MG-ADL) total score of 5 or greater at initiation (FDA, 2021); AND
4. There is confirmation of a positive AChR-ab (anti-acetylcholine receptor antibodies) test (Howard, 2017); AND
5. Individual has had an inadequate treatment response to an acetylcholinesterase inhibitor and at least TWO immunosuppressive therapies either in combination or as monotherapy, such as (Howard, 2017; Liu, 2010):
a. Azathioprine
b. Cyclosporine
c. Mycophenolate mofetil
d. Tacrolimus
e. Methotrexate
f. Cyclophosphamide
g. Glucocorticoids
6. The individual has had an inadequate response to chronic IVIG and/or plasmapheresis/plasma exchange over 12 months (Howard, 2021; Liu, 2010); AND
7. Individual will not be receiving IVIG or any another biologic agent for gMG in combination with this product; AND
8. Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for 1 year:
 
1. All the above requirements have previously been met; AND
2. The individual has evidence of benefit of the following:
a. Clinically significant improvement in the signs and symptoms of myasthenia gravis as documented in the medical record by a neurologist with specialization in the treatment of myasthenia gravis (i.e., Individual has had fewer relapses while on efgartigimod)  
b. Improvement and/or maintenance of at least a 2-point improvement (reduction in score) in the MG-ADL score from pre-treatment baseline.
c. IVIG or any other biologic agent for gMG is not being used in combination with efgartigimod.
 
Dosage and Administration
Dosing per FDA Guidelines
 
Efgartigimod (e.g., Vyvgart)
 
    • The recommended dosage for efgartigimod is 10 mg/kg administered as an intravenous infusion over one hour once weekly for 4 weeks. In individuals weighing 120 kg or more, the recommended dose is 1200 mg (3 vials) per infusion.
    • Administer subsequent treatment cycles based on clinical evaluation. The safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established.
    • If a scheduled infusion is missed, Efgartigimod may be administered up to 3 days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed.
    • Intravenous efgartigimod comes in a single dose vial of 400 mg/20 mL (20mg/mL) and should be administered by a healthcare professional.
 
Efgartigimod alfa and hyaluronidase-qvfc (e.g., Vyvgart Hytrulo)
 
    • The recommended dosage for efgartigimod alfa and hyaluronidase-gvfc 1,008 mg/11,200 units (1,008 mg efgartigimod alfa and 11,200 units hyaluronidase) administered subcutaneously over approximately 30 to 90 seconds in cycles of once weekly injections for 4 weeks.
    • Administer subsequent treatment cycles based on clinical evaluation; the safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established.
    • Efgartigimod alfa and hyaluronidase-gvfc is available as 1,008 mg efgartigimod alfa and 11,200 units hyaluronidase per 5.6 mL (180 mg/2,000 units per mL) in a single-dose vial.
 
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
 
Efgartigimod and efgartigimod and hyaluronidase, 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, efgartigimod and efgartigimod and hyaluronidase for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
*Clinical Classification of MG (Jayam Trouth 2021)
 
    • Class I MG is characterized by the following:
      • Any ocular muscle weakness
      • May have weakness of eye closure
      • All other muscle strengths are normal
    • Class II MG is characterized by the following:
      • Mild weakness affecting muscles other than ocular muscles
      • May also have ocular muscle weakness of any severity
    • Class IIa MG is characterized by the following:
      • Predominantly affecting limb, axial muscles, or both
      • May also have lesser involvement of oropharyngeal muscles
    • Class IIb MG is characterized by the following:
      • Predominantly affecting oropharyngeal, respiratory muscles, or both
      • May also have lesser or equal involvement of limb, axial muscles, or both
    • Class III MG is characterized by the following:
      • Moderate weakness affecting muscles other than ocular muscles
      • May also have ocular muscle weakness of any severity
    • Class IIIa MG is characterized by the following:
      • Predominantly affecting limb, axial muscles, or both
      • May also have lesser involvement of oropharyngeal muscles
    • Class IIIb MG is characterized by the following:
      • Predominantly affecting oropharyngeal, respiratory muscles, or both
      • May also have lesser or equal involvement of limb, axial muscles, or both
    • Class IV MG is characterized by the following:
      • Severe weakness affecting muscles other than ocular muscles
      • May also have ocular muscle weakness of any severity
    • Class IVa MG is characterized by the following:
      • Predominantly affecting limb, axial muscles, or both
      • May also have lesser involvement of oropharyngeal muscles
    • Class IVb MG is characterized by the following:
      • Predominantly affecting oropharyngeal, respiratory muscles or both
      • May also have lesser or equal involvement of limb, axial muscles, or both.
    • Class V MG is characterized by the following:
      • Intubation with or without mechanical ventilation, except when employed during routine postoperative management.
      • The use of feeding tube without intubation places the individual in class IVb.
 
**MG ADL Score (Wolfe 1999)
Grade
   
Talking
    • 0 normal
    • 1 intermittent slurring or nasal speech
    • 2 constant slurring or nasal, but can be understood
    • 3 difficult to understand speech
 
Chewing
    • 0 normal
    • 1 fatigue with solid food
    • 2 fatigue with soft food
    • 3 gastric tube
 
Swallowing
    • 0 normal
    • 1 rare episode of choking
    • 2 frequent choking, necessitating changes in diet
    • 3 gastric tube
 
Breathing
    • 0 normal
    • 1 shortness of breath with exertion
    • 2 shortness of breath at rest
    • 3 ventilator dependence
 
Impairment of ability to brush teeth or comb hair
    • 0 none
    • 1 extra effort, but no rest periods needed
    • 2 rest periods needed
    • 3 cannot do one of these function
 
Impairment of ability to arise from a chair
    • 0 none
    • 1 mild, sometimes uses arms
    • 2 moderate, always uses arms
    • 3 severe, requires assistance
 
Double vision
    • 0 None
    • 1 occurs, but not daily
    • 2 daily, but not constant
    • 3 constant
 
Eyelid droop
    • 0 none
    • 1 occurs, but not daily
    • 2 daily, but not constant
    • 3 constant
 
Effective October 19, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Efgartigimod in the treatment of refractory generalized myasthenia gravis (gMG) 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:
 
INITIAL APPROVAL for up to 12 months:
 
  1.   Individual is >18 years of age (FDA, 2021), AND  
  2.   A diagnosis of refractory chronic generalized Myasthenia Gravis is confirmed by a neurologist with specialization in the treatment of myasthenia gravis with Class II-IV disease (per *MGFA criteria), AND
  3.   The individual has a myasthenia Gravis-Specific Activities of Daily Living scale (**MG-ADL) total score of 5 or greater at initiation (FDA, 2021), AND
  4.   There is confirmation of a positive AChR-ab (anti-acetylcholine receptor antibodies) test (Howard, 2017) AND  
  5.   Individual has had an inadequate treatment response to an acetylcholinesterase inhibitor and at least TWO immunosuppressive therapies either in combination or as monotherapy, such as (Howard, 2017; Liu, 2010):
        •   Azathioprine
        •   Cyclosporine
        •   Mycophenolate mofetil
        •   Tacrolimus
        •   Methotrexate
        •   Cyclophosphamide
        •   Glucocorticoids
6.   The individual has had an inadequate response to chronic IVIG and/or plasmapheresis/plasma exchange over 12 months (Howard, 2021; Liu, 2010) AND
7.   Individual will not be receiving IVIG or any another biologic agent for gMG in combination with this product.
 
CONTINUED APPROVAL for 1 year:
 
  1.   All the above requirements have previously been met
  2.   The individual has evidence of benefit of the following:
a.  Clinically significant improvement in the signs and symptoms of myasthenia gravis as documented in the medical record by a neurologist with specialization in the treatment of myasthenia gravis (i.e., Individual has had fewer relapses while on efgartigimod)  
b.  Improvement and/or maintenance of at least a 2-point improvement (reduction in score) in the MG-ADL score from pre-treatment baseline.
c.  IVIG or any other biologic agent for gMG is not being used in combination with efgartigimod.
 
Dosage and Administration
  •   The recommended dosage is 10 mg/kg administered as an intravenous infusion over one hour once weekly for 4 weeks. In patients weighing 120 kg or more, the recommended dose is 1200 mg (3 vials) per infusion.
  •   Administer subsequent treatment cycles based on clinical evaluation. The safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established.   
  •   If a scheduled infusion is missed, Efgartigimod may be administered up to 3 days after the scheduled time point.  Thereafter, resume the original dosing schedule until the treatment cycle is completed.
 
Intravenous efgartigimod comes in a single dose vial of 400 mg/20 mL (20mg/mL) and should be administered 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
 
Efgartigimod 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, for any other indication or circumstance not described above, is considered investigational.  
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
*Clinical Classification of MG (Jayam Trouth 2021)
  • Class I MG is characterized by the following:
      • Any ocular muscle weakness
      • May have weakness of eye closure
      • All other muscle strengths are normal
  • Class II MG is characterized by the following:
      • Mild weakness affecting muscles other than ocular muscles
      • May also have ocular muscle weakness of any severity
  • Class IIa MG is characterized by the following:
      • Predominantly affecting limb, axial muscles, or both
      • May also have lesser involvement of oropharyngeal muscles
  • Class IIb MG is characterized by the following:
      • Predominantly affecting oropharyngeal, respiratory muscles, or both
      • May also have lesser or equal involvement of limb, axial muscles, or both
  • Class III MG is characterized by the following:
      • Moderate weakness affecting muscles other than ocular muscles
      • May also have ocular muscle weakness of any severity
  • Class IIIa MG is characterized by the following:
      • Predominantly affecting limb, axial muscles, or both
      • May also have lesser involvement of oropharyngeal muscles
  • Class IIIb MG is characterized by the following:
      • Predominantly affecting oropharyngeal, respiratory muscles, or both
      • May also have lesser or equal involvement of limb, axial muscles, or both
  • Class IV MG is characterized by the following:
      • Severe weakness affecting muscles other than ocular muscles
      • May also have ocular muscle weakness of any severity
  • Class IVa MG is characterized by the following:
      • Predominantly affecting limb, axial muscles, or both
      • May also have lesser involvement of oropharyngeal muscles
  • Class IVb MG is characterized by the following:
      • Predominantly affecting oropharyngeal, respiratory muscles or both
      • May also have lesser or equal involvement of limb, axial muscles, or both
  • Class V MG is characterized by the following:
      • Intubation with or without mechanical ventilation, except when employed during routine postoperative management
      • The use of feeding tube without intubation places the patient in class IVb.
 
**MG ADL Score (Wolfe 1999)
Grade   
Talking
    • 0 normal
    • 1 intermittent slurring or nasal speech
    • 2 constant slurring or nasal, but can be understood
    • 3 difficult to understand speech
Chewing
    • 0 normal
    • 1 fatigue with solid food
    • 2 fatigue with soft food
    • 3 gastric tube
Swallowing
    • 0 normal
    • 1 rare episode of choking
    • 2 frequent choking, necessitating changes in diet
    • 3 gastric tube
Breathing
    • 0 normal
    • 1 shortness of breath with exertion
    • 2 shortness of breath at rest
    • 3 ventilator dependence
Impairment of ability to brush teeth or comb hair
    • 0 none
    • 1 extra effort, but no rest periods needed
    • 2 rest periods needed
    • 3 cannot do one of these function
Impairment of ability to arise from a chair
    • 0 none
    • 1 mild, sometimes uses arms
    • 2 moderate, always uses arms
    • 3 severe, requires assistance
Double vision
    • 0 None
    • 1 occurs, but not daily
    • 2 daily, but not constant
    • 3 constant
Eyelid droop
    • 0 none
    • 1 occurs, but not daily
    • 2 daily, but not constant
    • 3 constant
 
 
Effective February 2, 2022 - October 18, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Efgartigimod meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of refractory chronic generalized myasthenia gravis (gMG) in adult patients when the following criteria are met:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
    • 18 years of age and older AND
    •  A diagnosis of refractory chronic generalized Myasthenia Gravis is confirmed by a neurologist with specialization in the treatment of myasthenia gravis with Class II-IV disease (per MGFA criteria), AND member has a myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score of 5 or greater at initiation (FDA, 2020), AND
    • There is confirmation of a positive AChR-ab (anti-acetylcholine receptor antibodies) (Howard, 2017) test and a negative MuSK (muscle-specific tyrosine kinase) antibody test. (If member is MuSK positive, then efgartigimod is only available if the member has failed or intolerant of rituximab and meets ALL of the other criteria) (Sanders, 2016) AND
    • The individual is on stable dose of MG therapy prior to screening, that included acetylcholinesterase (AChE) inhibitors, steroids, or non-steroidal immunosuppressive therapies (NSISTs), either in combination or alone (Howard, 2021) AND
    • The individual has documentation of inadequate response to treatment, is intolerant of, or has a published contraindication to at least 2 chronic disease modifying agents (e.g. glucocorticoids, azathioprine, mycophenolate, cyclosporine, methotrexate, tacrolimus) over at least 12 months [either combination or monotherapy] (Howard, 2017; Sanders, 2016), AND
    • The individual has had an inadequate response to chronic IVIG or plasmapheresis/plasma exchange over 12 months (Howard, 2021; Liu, 2010) AND
    • The individual will not be receiving IVIG or eculizumab in combination with this product.
 
*Clinical Classification of MG (Jayam Trouth 2021)
    • Class I MG is characterized by the following:
        • Any ocular muscle weakness
        • May have weakness of eye closure
        • All other muscle strengths are normal
    • Class II MG is characterized by the following:
        • Mild weakness affecting muscles other than ocular muscles
        • May also have ocular muscle weakness of any severity
    • Class IIa MG is characterized by the following:
        • Predominantly affecting limb, axial muscles, or both
        • May also have lesser involvement of oropharyngeal muscles
    • Class IIb MG is characterized by the following:
        • Predominantly affecting oropharyngeal, respiratory muscles, or both
        • May also have lesser or equal involvement of limb, axial muscles, or both
    • Class III MG is characterized by the following:
        • Moderate weakness affecting muscles other than ocular muscles
        • May also have ocular muscle weakness of any severity
    • Class IIIa MG is characterized by the following:
        • Predominantly affecting limb, axial muscles, or both
        • May also have lesser involvement of oropharyngeal muscles
    • Class IIIb MG is characterized by the following:
        • Predominantly affecting oropharyngeal, respiratory muscles, or both
        • May also have lesser or equal involvement of limb, axial muscles, or both
    • Class IV MG is characterized by the following:
        • Severe weakness affecting muscles other than ocular muscles
        • May also have ocular muscle weakness of any severity
    • Class IVa MG is characterized by the following:
        • Predominantly affecting limb, axial muscles, or both
        • May also have lesser involvement of oropharyngeal muscles
    • Class IVb MG is characterized by the following:
        • Predominantly affecting oropharyngeal, respiratory muscles or both
        • May also have lesser or equal involvement of limb, axial muscles, or both
    • Class V MG is characterized by the following:
        • Intubation with or without mechanical ventilation, except when employed during routine postoperative management
        • The use of feeding tube without intubation places the patient in class IVb.
 
**MG ADL Score (Wolfe 1999)
Grade   
Talking
    • 0 normal
    • 1 intermittent slurring or nasal speech
    • 2 constant slurring or nasal, but can be understood
    • 3 difficult to understand speech
Chewing
    • 0 normal
    • 1 fatigue with solid food
    • 2 fatigue with soft food
    • 3 gastric tube
Swallowing
    • 0 normal
    • 1 rare episode of choking
    • 2 frequent choking, necessitating changes in diet
    • 3 gastric tube
Breathing
    • 0 normal
    • 1 shortness of breath with exertion
    • 2 shortness of breath at rest
    • 3 ventilator dependence
Impairment of ability to brush teeth or comb hair
    • 0 none
    • 1 extra effort, but no rest periods needed
    • 2 rest periods needed
    • 3 cannot do one of these function
Impairment of ability to arise from a chair
    • 0 none
    • 1 mild, sometimes uses arms
    • 2 moderate, always uses arms
    • 3 severe, requires assistance
Double vision
    • 0 None
    • 1 occurs, but not daily
    • 2 daily, but not constant
    • 3 constant
Eyelid droop
    • 0 none
    • 1 occurs, but not daily
    • 2 daily, but not constant
    • 3 constant
 
CONTINUED APPROVAL (1 year):
 
    • Individual continues to meet the above criteria.
 
Dosage and Administration
 
    • The recommended dosage is 10 mg/kg administered as an intravenous infusion over one hour once weekly for 4 weeks. In patients weighing 120 kg or more, the recommended dose is 1200 mg per infusion.
    • Administer subsequent treatment cycles based on clinical evaluation. The safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established.  
    • If a scheduled infusion is missed, Efgartigimod may be administered up to 3 days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed.
 
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
 
Efgartigimod does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any indication or circumstance other than those listed above.
 
For members with contracts without primary coverage criteria, Efgartigimod is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective January 12, 2022 to February 1, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Efgartigimod meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of generalized myasthenia gravis (gMG) in adult patients when the following criteria are met:
 
INITIAL APPROVAL (6 months):
 
    • 18 years of age and older AND
    • Are anti-acetycholine receptor (AChR) antibody positive AND
    • *Myasthenia Gravis Foundation of America (MGFA) clinical classification class II to IV
    • **MG-Activities of Daily Living (MG-ADL) total score of ≥ 5 AND
    • Are on stable dose of MG therapy prior to screening, that included acetylcholinesterase (AChE) inhibitors, steroids, or non-steroidal immunosuppressive therapies (NSISTs), either in combination or alone (Howard, 2021) AND
    • Have IgG levels of at least 6 g/L AND
    • Prescribed by a neurologist.
 
*Clinical Classification of MG (Jayam Trouth 2021)
    • Class I MG is characterized by the following:
        • Any ocular muscle weakness
        • May have weakness of eye closure
        • All other muscle strengths are normal
    • Class II MG is characterized by the following:
        • Mild weakness affecting muscles other than ocular muscles
        • May also have ocular muscle weakness of any severity
    • Class IIa MG is characterized by the following:
        • Predominantly affecting limb, axial muscles, or both
        • May also have lesser involvement of oropharyngeal muscles
    • Class IIb MG is characterized by the following:
        • Predominantly affecting oropharyngeal, respiratory muscles, or both
        • May also have lesser or equal involvement of limb, axial muscles, or both
    • Class III MG is characterized by the following:
        • Moderate weakness affecting muscles other than ocular muscles
        • May also have ocular muscle weakness of any severity
    • Class IIIa MG is characterized by the following:
        • Predominantly affecting limb, axial muscles, or both
        • May also have lesser involvement of oropharyngeal muscles
    • Class IIIb MG is characterized by the following:
        • Predominantly affecting oropharyngeal, respiratory muscles, or both
        • May also have lesser or equal involvement of limb, axial muscles, or both
    • Class IV MG is characterized by the following:
        • Severe weakness affecting muscles other than ocular muscles
        • May also have ocular muscle weakness of any severity
    • Class IVa MG is characterized by the following:
        • Predominantly affecting limb, axial muscles, or both
        • May also have lesser involvement of oropharyngeal muscles
    • Class IVb MG is characterized by the following:
        • Predominantly affecting oropharyngeal, respiratory muscles or both
        • May also have lesser or equal involvement of limb, axial muscles, or both
    • Class V MG is characterized by the following:
        • Intubation with or without mechanical ventilation, except when employed during routine postoperative management
        • The use of feeding tube without intubation places the patient in class IVb.
 
**MG ADL Score (Wolfe 1999)
Grade   
Talking
    • 0 normal
    • 1 intermittent slurring or nasal speech
    • 2 constant slurring or nasal, but can be understood
    • 3 difficult to understand speech
Chewing
    • 0 normal
    • 1 fatigue with solid food
    • 2 fatigue with soft food
    • 3 gastric tube
Swallowing
    • 0 normal
    • 1 rare episode of choking
    • 2 frequent choking, necessitating changes in diet
    • 3 gastric tube
Breathing
    • 0 normal
    • 1 shortness of breath with exertion
    • 2 shortness of breath at rest
    • 3 ventilator dependence
Impairment of ability to brush teeth or comb hair
    • 0 none
    • 1 extra effort, but no rest periods needed
    • 2 rest periods needed
    • 3 cannot do one of these function
Impairment of ability to arise from a chair
    • 0 none
    • 1 mild, sometimes uses arms
    • 2 moderate, always uses arms
    • 3 severe, requires assistance
Double vision
    • 0 None
    • 1 occurs, but not daily
    • 2 daily, but not constant
    • 3 constant
Eyelid droop
    • 0 none
    • 1 occurs, but not daily
    • 2 daily, but not constant
    • 3 constant
 
CONTINUED APPROVAL (1 year):
 
    • Individual continues to meet the above criteria.
 
Dosage and Administration
 
    • The recommended dosage is 10 mg/kg administered as an intravenous infusion over one hour once weekly for 4 weeks. In patients weighing 120 kg or more, the recommended dose is 1200 mg per infusion.
    • Administer subsequent treatment cycles based on clinical evaluation. The safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established.  
    • If a scheduled infusion is missed, Efgartigimod may be administered up to 3 days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed.
 
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
 
Efgartigimod does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any indication or circumstance other than those listed above.
 
For members with contracts without primary coverage criteria, Efgartigimod is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
ADAPT was a randomized, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centers in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalized myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular) and were on a stable dose of at least one treatment for generalized myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588).
 
Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 [68%] of 65) in cycle 1 than in the placebo group (19 [30%] of 64), with an odds ratio of 4·95 (95% CI 2·21-11·53, p<0·0001). 65 (77%) of 84 patients in the efgartigimod group and 70 (84%) of 83 in the placebo group had treatment-emergent adverse events, with the most frequent being headache (efgartigimod 24 [29%] vs placebo 23 [28%]) and nasopharyngitis (efgartigimod ten [12%] vs placebo 15 [18%]). Four (5%) efgartigimod-treated patients and seven (8%) patients in the placebo group had a serious adverse event. Three patients in each treatment group (4%) discontinued treatment during the study. There were no deaths.
 
Efgartigimod was well tolerated and efficacious in patients with generalized myasthenia gravis. The individualized dosing based on clinical response was a unique feature of ADAPT, and translation to clinical practice with longer term safety and efficacy data will be further informed by the ongoing open-label extension. (Howard JF Jr, Bril V, Vu T, et.al, 2021)
 
October 2022 Update
The Institute for Clinical and Economic Review (ICER) published a review for eculizumab and efgartigimod for the treatment of myasthenia gravis.  It identified one Phase III trial each for eculizumab (REGAIN) and efgartigimod (ADAPT) but found insufficient data to compare these drugs to maintenance intravenous immunoglobulin IVIG and rituximab (RTX).  In the Phase III REGAIN trial, patients with anti-AChR antibody positive, treatment-resistant gMG who received eculizumab had significantly better improvement in the myasthenia gravis activities of daily living (MG-ADL) and quantitative myasthenia gravis (QMG) scores than those on placebo at four weeks and eight weeks, and the improvements were sustained at 26 weeks.  In addition, at week 26, the proportion of patients with minimal symptom expression (MG-ADL score of 0 or 1) was much greater in the eculizumab group (21.4% vs. 1.7%, p=0.0007) [Vissing J et al., 2020]  In the open label extension through 130 weeks of follow up, the benefits were maintained, and may have increased compared with 26 weeks [Mantegazza R, et al., 2021]  There were no excess adverse events (AEs) in the trials, although more patients in the eculizumab group stopped treatment due to AEs, and it carries a black box warning for meningococcal infections.  
 
The Phase III ADAPT trial was conducted in gMG patients with or without anti-AChR-antibody; however, the primary outcome was in the subgroup of anti-AChR antibody positive patients.  The proportion of patients with clinically meaningful improvement (≥2-point MG-ADL improvement sustained for ≥4 weeks) was much greater in the efgartigimod group compared to the placebo group.  Anti-AChR antibody positive gMG patients who received efgartigimod did significantly better on MG-ADL and QMG than those who received placebo.  However, the improvements were greater at four weeks than at eight weeks, reflecting the unusual dosing schedule in the trial.
 
Patients received their second treatment cycle only when they no longer had a clinically meaningful improvement on the MG-ADL.  Thus, many patients were back near baseline at eight weeks.  The anti-AChR antibody negative patients randomized to efgartigimod were only slightly more likely to respond based on the MG-ADL (68% vs. 63% in placebo group, p=NR).  AEs did not appear to be more common with efgartigimod, but there are long-term concerns about infections with lowering of IgG levels.
 
One important area of uncertainty is that it is not clear if or when to stop either of the drugs in patients who are responding to them.  For efgartigimod, the primary uncertainty is the appropriate dosing regimen.  In the ADAPT trial, subsequent cycles were started once patients lost clinical benefits.  It seems likely that in routine practice, patients and clinicians will not want to wait until the benefits have receded before starting another round of therapy.  Also, despite their use in clinical practice, there is a lack of comparative efficacy data for both rituximab and IVIG used as maintenance therapy for gMG.  
 
Taking into consideration the above information on the benefits and AEs of eculizumab, it was concluded that there is moderate certainty of a small or substantial net health benefit with high certainty of at least a small benefit for eculizumab added to conventional therapy (B+) in adults with gMG positive for anti-AChR antibodies “refractory” to conventional therapy.  For efgartigimod, given the above information on short-term benefits, but uncertainties about dosing, long-term benefits, and long-term safety, it was concluded that that there is moderate certainty of a comparable, small, or substantial net health benefit of efgartigimod added to conventional therapy with high certainty of at least comparable net health benefit (C++) in adults with gMG positive for anti-AChR antibodies.  While there is evidence for efgartigimod in adults with gMG negative for anti-AChR antibodies, it is sparse and of uncertain clinical and statistical significance.  Thus, it was concluded that the evidence was insufficient (I) to distinguish the net health benefit of efgartigimod added to conventional therapy from conventional therapy alone in patients who test negative for anti-AChR antibodies.  In addition, the evidence is insufficient (I) to distinguish the net health benefits of rituximab and IVIG from placebo, eculizumab, and efgartigimod.
 
2023 Update
Study 1 (NCT03669588) established the effectiveness of efgartigimod alfa-fcab for the treatment of generalized myasthenia gravis (gMG) in adults who are AChR antibody positive was conducted with efgartigimod alfa-fcab intravenous formulation. The pharmacological effect of efgartigimod alfa-fcab was assessed by measuring the decrease in serum IgG levels and AChR autoantibody levels. In patients testing positive for AChR antibodies and who were treated with efgartigimod alfa-fcab intravenous, there was a reduction in total IgG levels relative to baseline. Decrease in AChR autoantibody levels followed a similar pattern. A decrease in AChR-Ab was associated with a clinical response in AChR-Ab positive patients, as measured by the change from baseline in MGADL total score.  In Study 2, VYVGART HYTRULO demonstrated a comparable pharmacodynamic effect on AChR antibody reduction as compared to the efgartigimod alfa-fcab intravenous formulation, which established the efficacy of VYVGART HYTRULO. The pharmacological effect of VYVGART HYTRULO administered subcutaneously (SC) at 1,008 mg / 11,200 Units was compared to efgartigimod alfa-fcab administered intravenously at 10 mg/kg (EFG IV) in gMG patients. The maximum mean reduction in AChR-Ab level was observed at week 4, with a mean reduction of 62.2% and 59.7% in the VYVGART HYTRULO SC and efgartigimod alfa-fcab IV arm, respectively. The decrease in total IgG levels followed a similar pattern. The 90% confidence intervals for the geometric mean ratios of AChR-Ab reduction at day 29 and AUEC0-4w (area under the effect-time curve from time 0 to 4 weeks post dose) were within the range of 80% to 125%, indicating no clinically significant difference between the two formulations. (FDA, 2023)
 
2024 Update
There are substantial disease and health-related quality-of-life (HRQoL) burdens for many patients with myasthenia gravis (MG), especially for those whose disease symptoms are not well controlled. HRQoL measures such as the Myasthenia Gravis Quality of Life 15-item revised (MG-QOL15r) and EuroQoL 5-Dimensions 5-Levels (EQ-5D-5L) are vital for evaluating the clinical benefit of therapeutic interventions in patients with MG, as they assess the burden of disease and the effectiveness of treatment, as perceived by patients. The phase 3 ADAPT study (NCT03669588) demonstrated that efgartigimod-a novel neonatal Fc receptor inhibitor-was well tolerated and that acetylcholine receptor antibody-positive (AChR-Ab+) participants who received efgartigimod had statistically significant improvements in MG-specific clinical scale scores. The ancillary data reported, which cover an additional treatment cycle, show that these participants had similar significant improvements in HRQoL measures, the MG-QOL15r and EQ-5D-5L utility and visual analog scales, and that these improvements were maintained in the second treatment cycle. Positive effects on HRQoL were rapid, seen as early as the first week of treatment in both treatment cycles, and maintained for up to 4 weeks in the follow-up-only portion of treatment cycles. The pattern of improvements in HRQoL paralleled changes in immunoglobulin G level, and correlational analyses show that improvements were consistent across HRQoL measures and with clinical efficacy measures in the ADAPT study. The substantial and durable improvements in HRQoL end points in this study demonstrate the broader benefit of treatment with efgartigimod beyond relief of immediate signs and symptoms of gMG. (Saccà F, Barnett C, Vu T, 2023)
CPT/HCPCS:
C9399Unclassified drugs or biologicals
J3590Unclassified biologics
J9332Injection, efgartigimod alfa-fcab, 2mg
J9334Injection, efgartigimod alfa, 2 mg and hyaluronidase qvfc
References: Howard JF Jr, Bril V, Vu T, Karam C, Peric S, Margania T, Murai H, Bilinska M, Shakarishvili R, Smilowski M, Guglietta A, Ulrichts P, Vangeneugden T, Utsugisawa K, Verschuuren J, Mantegazza R; ADAPT Investigator Study Group.(2021) Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021 Jul;20(7):526-536. doi: 10.1016/S1474-4422(21)00159-9. Erratum in: Lancet Neurol. 2021 Aug;20(8):e5. PMID: 34146511.

Jayam Trouth, A., Dabi, A., Solieman, N., Kurukumbi, M., & Kalyanam, J(2012) Myasthenia gravis: a review. Autoimmune diseases, 2012, 874680. https://doi.org/10.1155/2012/874680

Liu JF, Wang WX, Xue J, Zhao CB, You HZ, Lu JH, Gu Y.(2010) Comparing the autoantibody levels and clinical efficacy of double filtration plasmapheresis, immunoadsorption, and intravenous immunoglobulin for the treatment of late-onset myasthenia gravis. Ther Apher Dial. 2010 Apr;14(2):153-60. doi: 10.1111/j.1744-9987.2009.00751.x. PMID: 20438536.

Mantegazza R, Wolfe GI, Muppidi S, et al.(2021) Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension. Neurology. 2021;96:e610-e618.

Saccà F, Barnett C, Vu T, Peric S, Phillips GA, Zhao S, Qi CZ, Gelinas D, Chiroli S, Verschuuren JJGM.(2023) Efgartigimod improved health-related quality of life in generalized myasthenia gravis: results from a randomized, double-blind, placebo-controlled, phase 3 study (ADAPT). J Neurol. 2023 Apr;270(4):2096-2105. doi: 10.1007/s00415-022-11517-w. Epub 2023 Jan 4. PMID: 36598575; PMCID: PMC10025199.

Sanders DB, Wolfe GI, Benatar M, et al for the Task Force of the Myasthenia Gravis Foundation of America (MGFA).(2016) International consensus guidance for management of myasthenia gravis. Neurology 2016; 87:419.

Tice JA, Touchette DR, Nikitin D, Campbell JD, Lien P-W, Moradi A, Rind DM, Pearson SD, Agboola F.(2021) Eculizumab and Efgartigimod for the Treatment of Myasthenia Gravis: Effectiveness and Value; Final Report. Institute for Clinical and Economic Review, September 10, 2021. Accessed October 10, 2022. https://icer.org/assessment/myasthenia-gravis/#timeline

U.S. Food and Drug Administration (FDA).(2023) (2023) Vyvgart Hytulo. Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761304s000lbl.pdf. Accessed October 6, 2023.

Vissing J, Jacob S, Fujita KP, et al.(2020) ‘Minimal symptom expression’ in patients with acetylcholine receptor antibody-positive refractory generalized myasthenia gravis treated with eculizumab. Journal of Neurology. 2020;267:1991-2001.

Vyvgart (Efgartigimod) [prescribing information] Argenx; 2021

Vyvgart Hytrulo (efgartigimod alfa and hyaluronidase) [prescribing information]. Boston, MA: Argenx US Inc; June 2023.

Wolfe GI et al.(1999) Myasthenia gravis activities of daily living profile. Neurology 1999: 52:1487; DOI: 10.1212/WNL.52.7.1487
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