Effective Date

Date of Origin   

10-01-2025           

10-01-2025

Vyvgart Hytrulo®

(efgartigimod alfa and hyaluronidase-qvfc)

Subcutaneous Injection

Treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive

Treatment of adult patients with chronic inflammatory demyelinating polyneuropathy (CIDP)

1

Generalized Myasthenia Gravis (gMG)

Myasthenia gravis (MG) is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. Although the disorder usually becomes apparent during adulthood, symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia), or may become more generalized (generalized myasthenia gravis [gMG]), involving multiple muscle groups. Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features commonly include weakness of facial muscles; impaired speech (dysarthria); difficulties chewing and swallowing (dysphagia); and weakness of the upper arms and legs (proximal limb weakness). In addition, about 10% of affected patients may develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis). Myasthenia gravis results from an abnormal immune reaction in which antibodies inappropriately attack and gradually injure certain receptors in muscles that receive nerve impulses (antibody-mediated autoimmune response).(2)

The course of myasthenia gravis is highly variable. For example, the degree of muscle weakness may vary over hours, from day to day, or over weeks and months, tending to increase with repeated muscle use and to improve with rest. In addition, particularly during the first years after disease onset, some affected individuals may experience alternating periods in which symptoms temporarily subside or worsen. A short-term aggravation of symptoms may be triggered by a variety of factors, including infection, excessive physical activity, menstruation, and after delivery of a child.(2)

Corticosteroids are a standard treatment for MG but may cause transient worsening within the first 2 weeks and patients should be monitored closely for this possibility. As a result, a MG consensus panel lists corticosteroids as one of many agents to avoid or use with caution in MG. A nonsteroidal immunosuppressive agent should be used initially in treating MG. Nonsteroidal immunosuppressive agents that can be used in MG include azathioprine, cyclosporine, mycophenolate mofetil, methotrexate, and tacrolimus. For nonsteroidal immunosuppressive agents, once treatment goals have been achieved and maintained for 6 months to 2 years, the immunosuppressive dose should be tapered slowly to the minimal effective amount. Patients must be monitored for potential adverse effects and complications from immunosuppressive drugs. Changing to an alternative immunosuppressive agent should be considered if adverse effects and complications are medically significant or create undue hardship for the patient.(3)

Plasma exchange and IVIg are appropriately used as short-term treatments in patients with MG with life-threatening signs such as respiratory insufficiency or dysphagia; in preparation for surgery in patients with significant bulbar dysfunction; when a rapid response to treatment is needed; when other treatments are insufficiently effective; and prior to beginning corticosteroids if deemed necessary to prevent or minimize exacerbations. The use of IVIg as maintenance therapy can be considered for patients with refractory MG or for those in whom immunosuppressive agents are contraindicated. Refractory MG is defined as post-intervention status is unchanged or worse after corticosteroids and at least 2 other immunosuppressive agents, used in adequate doses for an adequate duration, with persistent symptoms or side effects that limit functioning, as defined by the patient and physician.(3)

The time of onset and maximal effect varies between products. Azathioprine, mycophenolate mofetil, cyclosporine, and tacrolimus can take between 6 to 12 months to onset and up to 1 to 2 years to see maximal effect in MG. Rapid therapies such as plasmapheresis or IVIg therapy take approximately 1 week to onset and between 1 to 3 weeks to see maximal effect.(4)

Certain medications have established pharmacologic adverse effects on neuromuscular transmission. Use of these medications in a patient with MG can further reduce the effectiveness of neuromuscular transmission and cause increased clinical weakness. However, reported associations do not necessarily mean these medications should never be prescribed in MG. Clinical judgment and the risk-to-benefit ratio of the drug should be considered when it is deemed important for a patient’s treatment. Medications that can cause a significant increase in weakness in patients with MG include fluoroquinolones, botulinum toxin, ketolides (particularly telithromycin) and aminoglycoside antibiotics, beta blockers, macrolide antibiotics, procainamide, quinidine, quinine, and magnesium. A number of other medications may unmask or exacerbate MG, particularly the neuromuscular blocking agents used during anesthesia, which can lead to prolonged postoperative weakness and ventilator dependence.(3)

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired autoimmune disorder directed against the myelin sheath of peripheral nerves and nerve roots. The diagnosis of CIDP should be considered in patients with progressive symmetric or asymmetric polyradiculopathy who have a relapsing-remitting clinical course or that progresses for more than two months, particularly if the clinical features include positive sensory symptoms, proximal weakness, or areflexia.(5)

Electrophysiologic testing developed by the European Federation of Neurological Societies and the Peripheral Nerve Society (EFNS/PNS) is the most widely used diagnostic criteria in clinical practice. Definitive CIDP diagnosis has at least one of the following demyelination criteria based on electrodiagnostic findings:(5)

• Prolonged distal motor latency in at least 2 motor nerves
• Reduced motor conduction velocity in at least 2 motor nerves
• Prolonged F-wave latency in at least 2 motor nerves
• Absent F-wave in at least 2 motor nerves plus one other demyelination criterion listed here in at least 1 other nerve
• Partial motor conduction block in at least 2 motor nerves or in 1 nerve plus one other demyelination criterion listed here
• Abnormal temporal dispersion conduction in at least 2 motor nerves
• Distal CMAP duration increase in at least 1 nerve plus one other demyelination criterion listed here in at least 1 other nerve

Initial treatment for CIDP is immune modulating therapy with intravenous immunoglobulin (IVIG), glucocorticoids, or plasma exchange. Considerations that drive the selection of initial therapy include disease severity, comorbid disorders, venous access, potential adverse effects, availability, and cost. Guidelines recommend the use of a corticosteroid or IVIG for patients with moderate to severe CIDP. IVIG should be considered instead of a corticosteroid for patients with pure motor CIDP based on evidence of deterioration in these patients soon after initiation of a corticosteroid.(5) 

Efficacy

Vyvgart, an IgG1 Fc fragment, is designed for increased affinity for the neonatal Fc receptor (FcRn). It competes with IgG to occupy FcRn and reduce overall IgG recycling.(6)

The humoral immune response provides specific, long-lived protection against invading pathogens, via immunoglobulin production and other memory functions. IgG, the most abundant immunoglobulin isotype, has the longest half-life and protects against bacterial and viral infections. FcRn, by protecting IgG from intracellular degradation, results in an approximately 21-day circulating IgG half-life and high plasma levels.(7)

Dysregulated immune responses may lead to antibodies against self-antigens (autoantibodies), resulting in organ-specific or systemic autoimmune diseases. Autoantibody-mediated diseases have been treated by nonspecific immunoglobulin-lowering/modulating therapies, including immunoadsorption, plasma exchange, and high-dose intravenous immunoglobulin. However, targeting FcRn with specific inhibitors results in reduction in only IgG levels. The effectiveness of FcRn inhibitors in autoimmune diseases, including myasthenia gravis and immune thrombocytopenia, provides further evidence that IgG is a primary driver in those autoantibody-mediated diseases.(7)

In recent decades, IgG4 (the least prevalent IgG subclass) has been identified as the pathogenic driver in several autoimmune diseases, including pemphigus vulgaris, pemphigus foliaceus, and muscle-specific kinase MG. The contributions and pathogenicity of different immunoglobulin classes and IgG sub-classes to various diseases and their relationship to disease severity are not well understood.(7)

FcRn is a multifunctional atypical Fc-gamma receptor. FcRn was initially identified as responsible for IgG transport from maternal to fetal circulation across the placenta, and later for IgG recycling. Subsequently, additional roles of FcRn have been defined, including albumin recycling, bidirectional transport of IgG and albumin across a range of polarized cellular barriers, potentiating efficient responses to IgG-immune complexes and as a receptor for enteric cytopathic human orphan (echo) viruses.(7)

The ADAPT trial (NCT03669588) 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. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (greater than or equal to 2-point MG-ADL improvement sustained for greater than or equal to 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 Vyvgart or placebo.(8). Eligibility criteria included:(8,9)

• Patients aged at least 18 years with gMG regardless of anti-acetylcholine receptor antibody status
• Diagnosis of MG as defined by the Myasthenia Gravis Foundation of America (MGFA) class II, III, IVa, and IVb
• Confirmation of the diagnosis documented and supported by at least 1 of the following 3 tests:
  • History of abnormal neuromuscular transmission demonstrated by single-fiber electromyography or repetitive nerve stimulation
  • History of positive edrophonium chloride test
  • Demonstrated improvement in MG signs on oral AChE inhibitors as assessed by the treating physician
• A Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (greater than 50% non-ocular)
• On a stable dose of at least one treatment for gMG

MG Activities of Daily Living (MG-ADL):(4)

The MGFA clinical classification divides MG into 5 main classes and several subclasses. It is designed to identify subgroups of patients with MG who share distinct clinical features or severity of disease that may indicate different prognoses or responses to therapy.(10)

Of the acetylcholine receptor antibody-positive patients, more of those in the Vyvgart 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, p < than 0.0001).(8)

The individualized dosing based on clinical response was a unique feature for ADAPT, and translation to clinical practice with longer term safety and efficacy data will be further evaluated by the ongoing open-label extension study (ADAPT+).(8)

The ADAPTsc study (NCT04735432) is an interventional Phase 3, Randomized, Open-label, Parallel-Group Study to compare the Pharmacodynamics (PD), Pharmacokinetics (PK), safety, tolerability, immunogenicity, and clinical efficacy of Vyvgart co-formulated with recombinant human hyaluronidase PH20 (rHuPH20) as compared to Vyvgart IV infused in patient with generalized myasthenia gravis (gMG). The primary objective of the trial was to demonstrate that the PD effect of 1000 mg Vyvgart PH20 SQ (Vyvgart co-formulated with recombinant human hyaluronidase PH20 for subcutaneous administration), administered once weekly for 4 administrations, is noninferior to IV infusions of Vyvgart (Vyvgart formulation for intravenous infusion) at a dose of 10 mg/kg administered once weekly for 4 administrations.(11) 

The secondary objectives were to compare the PD effect of Vyvgart PH20 SC and Vyvgart IV over time: to evaluate the PK of Vyvgart PH20 SC and Vyvgart IV; to evaluate the safety, tolerability, and immunogenicity of Vyvgart PH20 SC and Vyvgart IV; to evaluate the clinical efficacy of Vyvgart PH20 SC and Vyvgart IV.(11) 

Inclusion criteria included:(11,12)

• Patient was at least 18 years of age at the time of signing informed consent form
• Diagnosis of gMG with confirmed documentation and supported by at least 1 of the following:
  • History of abnormal neuromuscular transmission demonstrated by single fiber electromyography or repetitive nerve stimulation
  • History of positive edrophonium chloride test
  • Demonstrated improvement in MG signs upon treatment with oral acetylcholinesterase (AChE) inhibitors as assessed by the treating physician
• A MG-ADL score of at least 5 (greater than 50% non-ocular)
• Meeting the clinical criteria as defined by the MGFA class II, III, IVa, or IVb

Exclusion criteria included:(11,12)

• Are pregnant or lactating, or intend to become pregnant during the study or within 90 days after last dose of Investigational Medicinal Product (IMP)
• Any of the following medical conditions:
  • Clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection at screening
  • Any other known autoimmune disease that, in the opinion of the investigator, would interfere with an accurate assessment of clinical symptoms of MG or put the participant at undue risk
  • History of malignancy unless deemed cured by adequate treatment with no evidence of reoccurrence for greater than or equal to 3 years before the first administration of the IMP. Participants with the following cancers could be included at any time:
    • Adequately treated basal cell or squamous cell skin cancer
    • Carcinoma in situ of the breast
    • Incidental histological findings of prostate cancer (TNM Classification of Malignant Tumors stage T1a or T1b)
  • Clinical evidence of other significant serious diseases, or the participant has had a recent major surgery, or who have any other condition that, in the opinion of the investigator, could confound the results of the study or put the participant at undue risk

The primary objective reported as percent change from baseline in total IgG levels at day 29 was -66.4 (-68.91 to -63.86) in the Vyvgart PH20 SC arm and -62.2 (-64.67 to -59.72) in the Vyvgart IV arm (p-value < 0.0001).(11)

Additionally, the efficacy of Vyvgart Hytrulo for the treatment of adults with CIDP was established in a two stage, multicenter study (Study 3; NCT04281472). Study 3 included an open-label period to identify Vyvgart Hytrulo responders (stage A) who then entered a randomized, double-blind, placebo-controlled, withdrawal period (stage B). In stage A, a total of 322 patients received up to 12 once weekly subcutaneous injections until evidence of improvement occurred at two consecutive study visits. Improvement was defined as aINCAT improvement greater than or equal to 1 point, I-RODS improvement greater than or equal to 4 points, or mean grip strength improvement greater than or equal to 8 kPa. Sixty-nine percent of patients (n=221) had documented improvement at two consecutive visits during stage A then entered stage B. In stage B of the trial the primary endpoint was the time to clinical deterioration defined as a 1 point increase in aINCAT at two consecutive visits or a greater than 1 point increase in aINCAT at one visit. Patients who received Vyvgart Hytrulo experienced a longer time to clinical deterioration compared to patients who received placebo, which was statistically significant.(1)

Safety

Vyvgart Hytrulo is contraindicated in patients with serious hypersensitivity to efgartigimod alfa products, to hyaluronidase, or to any of the excipients of Vyvgart Hytrulo.(1)

1

Vyvgart Hytrulo prescribing information. Argenx US, Inc. April 2025.

2

National Institute of Neurological Disorders and Stroke. Myasthenia Gravis Fact Sheet. NIH Publication No. 17-768. July 2018.

3

Narayanaswami P, Sanders DB, Wolfe G, et al. International Consensus Guidance for Management of Myasthenia Gravis. Neurology. 2021;96(3):114-122. doi:10.1212/wnl.0000000000011124.

4

Wincentsen J. MG Activities of Daily Living (MG-ADL) scale. Conquer Myasthenia Gravis. Published September 29, 2022. https://myastheniagravis.org/mg-activities-of-daily-living-mg-adl-scale/.

5

Van Den Bergh PYK, Van Doorn PA, Hadden RDM, et al. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision. Journal of the Peripheral Nervous System. 2021;26(3):242-268. doi:10.1111/jns.12455.

6

Ulrichts P, Guglietta A, Dreier T, et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. Journal of Clinical Investigation. 2018;128(10):4372-4386. doi:10.1172/jci97911.

7

Patel DD, Bussel JB. Neonatal Fc receptor in human immunity: Function and role in therapeutic intervention. Journal of Allergy and Clinical Immunology. 2020;146(3):467-478. doi:10.1016/j.jaci.2020.07.015.

8

Howard JF, Bril V, Vu T, et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurology. 2021;20(7):526-536. doi:10.1016/s1474-4422(21)00159-9.

9

An efficacy and safety study of ARGX-113 in patients with myasthenia gravis who have generalized muscle weakness - Full text view - ClinicalTrials.gov. https://classic.clinicaltrials.gov/ct2/show/NCT03669588.

10

Jayam Trouth A, Dabi A, Solieman N, Kurukumbi M, Kalyanam J. Myasthenia gravis: a review. Autoimmune Dis. 2012;2012:874680. doi:10.1155/2012/874680.

11

Evaluating the pharmacodynamic noninferiority of Efgartigimod PH20 SC administered subcutaneously as compared to Efgartigimod administered intravenously in patients with generalized myasthenia gravis - full text view - ClinicalTrials.gov. https://classic.clinicaltrials.gov/ct2/show/NCT04735432.

12

A safety and tolerability study of ARGX-113 in patients with myasthenia gravis who have generalized muscle weakness. - Full text view - ClinicalTrials.gov. https://classic.clinicaltrials.gov/ct2/show/NCT03770403.

Vyvgart hytrulo

efgartigimod alf-hyalur-qvfc pref syr

1000-10000 MG-UNT/5ML

M ; N ; O ; Y

N

Vyvgart hytrulo

efgartigimod alf-hyalur-qvfc pref syr

1000-10000 MG-UNT/5ML

4

Syringes

28

DAYS

Vyvgart hytrulo

efgartigimod alf-hyalur-qvfc pref syr

1000-10000 MG-UNT/5ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance

Vyvgart hytrulo

efgartigimod alf-hyalur-qvfc pref syr

1000-10000 MG-UNT/5ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. ONE of the following:
   1. The patient has a diagnosis of generalized Myasthenia Gravis (gMG) AND ALL of the following:
      1. The patient has a positive serological test for anti-AChR antibodies (medical records required) AND
      2. The patient has a Myasthenia Gravis Foundation of America (MGFA) clinical classification class of II-IVb AND
      3. The patient has a MG-Activities of Daily Living total score of greater than or equal to 5 AND
      4. ONE of the following:
         1. The patient’s current medications have been assessed and any medications known to exacerbate myasthenia gravis (e.g., beta blockers, procainamide, quinidine, magnesium, anti-programmed death receptor-1 monoclonal antibodies, hydroxychloroquine, aminoglycosides) have been discontinued OR
         2. Discontinuation of the offending agent is NOT clinically appropriate AND
      5. ONE of the following:
         1. The patient has tried and had an inadequate response to at least ONE conventional agent used for the treatment of myasthenia gravis (i.e., corticosteroids, azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, methotrexate, cyclophosphamide) OR
         2. The patient has an intolerance or hypersensitivity to ONE conventional agent used for the treatment of myasthenia gravis (i.e., corticosteroids, azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, methotrexate, cyclophosphamide) OR
         3. The patient has an FDA labeled contraindication to ALL conventional agents used for the treatment of myasthenia gravis (i.e., corticosteroids, azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, methotrexate, cyclophosphamide) OR
         4. The patient required chronic intravenous immunoglobulin (IVIG) OR
         5. The patient required chronic plasmapheresis/plasma exchange AND
      6. The patient will NOT be using the requested agent in combination with Rystiggo (rozanolixizumab-noli), Soliris (eculizumab), Bkemv (eculizumab-aeeb), Epysqli (eculizumab-aagh), Ultomiris (ravulizumab-cwvz), or Zilbrysq (zilucoplan) for the requested indication OR
   2. The patient has a diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP), AND ALL of the following:
      1. The patient's disease course is progressive or relapsing and remitting for at least 2 months AND
      2. The patient has progressive or relapsing motor sensory impairment of more than one limb AND
      3. The patient has electrodiagnostic findings indicating demyelination with at least ONE of the following:
         1. Prolonged distal motor latency in at least 2 motor nerves OR
         2. Reduced motor conduction velocity in at least 2 motor nerves OR
         3. Prolonged F-wave latency in at least 2 motor nerves OR
         4. Absent F-wave in at least 2 motor nerves plus one other demyelination criterion listed here in at least 1 other nerve OR
         5. Partial motor conduction block in at least 2 motor nerves or in 1 nerve plus one other demyelination criterion listed here OR
         6. Abnormal temporal dispersion conduction in at least 2 motor nerves OR
         7. Distal CMAP duration increase in at least 1 nerve plus one other demyelination criterion listed here in at least 1 other nerve AND
      4. ONE of the following:
         1. The patient has tried and failed at least a 3-month trial of ONE standard of care therapy (i.e., corticosteroids, immunoglobulins, plasma exchange) OR
         2. The patient has an intolerance or hypersensitivity to ONE standard of care therapy (i.e., corticosteroids, immunoglobulins, plasma exchange) OR
         3. The patient has an FDA labeled contraindication to ALL standard of care therapies (i.e., corticosteroids, immunoglobulins, plasma exchange) OR
   3. The patient has another FDA labeled indication for the requested agent and route of administration AND
2. If the patient has an FDA labeled indication, then ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. There is support for using the requested agent for the patient’s age for the requested indication AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 6 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

*Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. The patient has had clinical benefit with the requested agent AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient will NOT be using the requested agent in combination with Rystiggo (rozanolixizumab-noli), Soliris (eculizumab), Bkemv (eculizumab-aeeb), Epysqli (eculizumab-aagh), Ultomiris (ravulizumab-cwvz), or Zilbrysq (zilucoplan) for the requested indication AND
5. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Universal QL

Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
   1. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
   2. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
   3. BOTH of the following:
      1. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication

Length of Approval: up to 12 months