Efgartigimod Alfa-fcab (Vyvgart) and Efgartigimod Alfa and Hyaluronidase-qvfc (Vyvgart Hytrulo)

Number: 1002

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 efgartigimod alfa-fcab (Vyvgart) and efgartigimod alfa and hyaluronidase-qvfc (Vyvgart Hytrulo) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of efgartigimod alfa-fcab (Vyvgart) or efgartigimod alfa and hyaluronidase-qvfc (Vyvgart Hytrulo) is required of all Aetna participating providers and members in applicable plan designs. For precertification of either medication, 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 to Vyvgart Hytrulo for chronic inflammatory demyelinating polyneuropathy (CIDP) indication only. For information on site of service for Vyvgart Hytrulo for CIDP, see Utilization Management Policy on Site of Care for Specialty Drug Infusions. 

1. Criteria for Initial Approval

   Generalized myasthenia gravis (gMG)

   Aetna considers efgartigimod alfa-fcab (Vyvgart) or efgartigimod alfa and hyaluronidase-qvfc (Vyvgart Hytrulo) medically necessary for treatment of generalized myasthenia gravis (gMG) when all of the following criteria are met: 

   1. Anti-acetylcholine receptor (AChR) antibody positive; and
   2. Myasthenia Gravis Foundation of America (MGFA) clinical classification II to IV; and
   3. MG activities of daily living (MG-ADL) total score of greater than or equal to 5; and
   4. Meets one of the following:
      
      
      1. Member has had an inadequate response or intolerable adverse event to at least two immunosuppressive therapies over the course of at least 12 months (e.g., azathioprine, corticosteroids, cyclosporine, methotrexate, mycophenolate, tacrolimus; or
      2. Member has had an inadequate response or intolerable adverse event to at least one immunosuppressive therapy and intravenous immunoglobulin (IVIG) over the course of at least 12 months; or
      3. Member has a documented clinical reason to avoid therapy with immunosuppressive agents and IVIG; and

   5. The requested requested medication will not be used in combination with another neonatal Fc receptor blocker (e.g., Rystiggo) or complement inhibitor (e.g., Soliris, Ultomiris, Zilbrysq.

   Chronic inflammatory demyelinating polyneuropathy (CIDP)

   Aetna considers efgartigimod alfa and hyaluronidase-qvfc (Vyvgart Hytrulo) medically necessary for treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) when all of the following criteria are met:

   1. Disease course is progressive or relapsing/remitting for 2 months or longer; and
   2. Diagnosis was confirmed by electrodiagnostic testing (consistent with European Federation of Neurological Societies/Peripheral Nerve Society [EFNS/PNS] guidelines); and
   3. Meets one of the following:
      
      
      1. Member has had an inadequate response or intolerable adverse event to immunoglobulins, corticosteroids, or plasma exchange; or
      2. Member has a documented clinical reason to avoid therapy with immunoglobulins, corticosteroids, or plasma exchange.

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

2. Continuation of Therapy

   1. Generalized myasthenia gravis (gMG)

      Aetna considers continuation of efgartigimod alfa-fcab (Vyvgart) or efgartigimod alfa and hyaluronidase-qvfc (Vyvgart Hytrulo) therapy medically necessary for treatment of gMG in members requesting reauthorization when all of the following criteria are met:

      1. There is no evidence of unacceptable toxicity or disease progression while on the current regimen; and
      2. Member demonstrates a positive response to therapy (e.g., improvement in MG-ADL score, MG Manual Muscle Test (MMT), MG Composite); and
      3. The requested requested medication will not be used in combination with another neonatal Fc receptor blocker (e.g., Rystiggo) or complement inhibitor (e.g., Soliris, Ultomiris, Zilbrysq);

   2. Chronic inflammatory demyelinating polyneuropathy (CIDP)

      Aetna considers continuation of efgartigimod alfa and hyaluronidase-qvfc (Vyvgart Hytrulo) therapy medically necessary for treatment of CIDP when all of the following criteria are met:

      1. There is no evidence of unacceptable toxicity or disease progression while on the current regimen; and
      2. Member demonstrates a positive response to therapy (e.g., improvement in Inflammatory Rasch-built Overall Disability Scale (I-RODS), Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale, Medical Research Council (MRC) Sum score, grip strength).

3. Related Policies

   1. CPB 0206 - Parenteral Immunoglobulins
   2. CPB 0285 - Plasmapheresis/Plasma Exchange/Therapeutic Apheresis
   3. CPB 0314 - Rituximab
   4. CPB 0807 - Eculizumab
   5. CPB 0946 - Ravulizumab-cwvz (Ultomiris)
   6. CPB 1035 - Rozanolixizumab-noli (Rystiggo)

Dosage and Administration

Vyvgart

Vyvgart is supplied as a 20 mL single-dose vial which contains 400 mg of efgartigimod alfa-fcab at a concentration of 20 mg/mL. Vyvgart is diluted with 0.9% Sodium Chloride Injection, USP prior to administration. Vyvgart is for intravenous infusion only.

Generalized myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AChR) antibody positive: 

• The recommended dosage of Vyvgart is 10 mg/kg administered as an intravenous infusion over one hour once weekly for 4 weeks. In persons weighing 120 kg or more, the recommended dose of Vyvgart is 1200 mg (3 vials) per infusion.
• Subsequent treatment cycles are administered 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, Vyvgart may be administered up to 3 days after the scheduled time point. Thereafter, the original dosing schedule is resumed until the treatment cycle is completed.

Source: argenx US, 2024a

Vyvgart Hytrulo

Vyvgart Hytrulo is supplied 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. Vyvgart Hytrulo is for subcutaneous injection and is to be administered by a healthcare professional only.

Generalized myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AChR) antibody positive:

• The recommended dosage of Vyvgart Hytrulo is 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.
• Subsequent treatment cycles are administered according to 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, Vyvgart Hytrulo may be administered up to 3 days after the scheduled time point. Thereafter, the original dosing schedule is resumed until the treatment cycle is completed.

Chronic inflammatory demyelinating polyneuropathy (CIDP):

• The recommended dosage of Vyvgart Hytrulo is 1,008 mg / 11,200 units (1,008 mg efgartigimod alfa and 11,200 units hyaluronidase) administered once weekly as a subcutaneous injection over approximately 30 to 90 seconds
• If a scheduled injection is missed, Vyvgart Hytrulo may be administered up to 3 days after the scheduled time point. Thereafter, resume the original dosing schedule.  as once weekly injections.  

Source: argenx US, 2024b

Experimental, Investigational, or Unproven

Aetna considers efgartigimod experimental, investigational, or unproven for the treatment of pemphigus vulgaris and pemphigus foliaceus.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Efgartigimod alfa-fcab (Vyvgart):
Other CPT codes related to the CPB:
95851	Range of motion measurements and report (separate procedure); each extremity (excluding hand) or each trunk section (spine)
95852	Range of motion measurements and report (separate procedure); hand, with or without comparison with normal side
96360	Intravenous infusion, hydration; initial, 31 minutes to 1 hour
96361	Intravenous infusion, hydration; each additional hour (List separately in addition to code for primary procedure)
96365 – 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
HCPCS codes covered if selection criteria are met:
J9332	Injection, efgartigimod alfa-fcab, 2mg
Other HCPCS codes related to the CPB:
Zilbrysq (zilucoplan) –no specific code
J1300	Injection, eculizumab, 10 mg
J1303	Injection, ravulizumab-cwvz, 10 mg
J9333	Injection, rozanolixizumab-noli, 1 mg
ICD-10 codes covered if selection criteria are met:
G70.00 – G70.01	Myasthenia gravis
ICD-10 codes not covered for indications listed in the CPB:
L10.0	Pemphigus vulgaris
L10.2	Pemphigus foliaceous
Hyaluronidase-qvfc (Vyvgart Hytrulo):
Other CPT codes related to the CPB:
36514	Therapeutic apheresis; for plasma pheresis
90283	Immune globulin (IgIV), human, for intravenous use
95860 – 95872	Needle electromyography
95885 – 95887	Needle electromyography, each extremity, with related paraspinal areas, when performed, done with nerve conduction, amplitude and latency/velocity study
95905	Motor and/or sensory nerve conduction, using preconfigured electrode array(s), amplitude and latency/velocity study, each limb, includes F-wave study when performed, with interpretation and report
95907 – 95913	Nerve conduction studies
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J9334	Injection, efgartigimod alfa, 2 mg and hyaluronidase-qvfc
Other HCPCS codes related to the CPB:
Zilbrysq (zilucoplan) – no specific code
J0702	Injection, betamethasone acetate 3 mg and betamethasone sodium phosphate 3 mg
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphate, 1 mg
J1300	Injection, eculizumab, 10 mg
J1303	Injection, ravulizumab-cwvz, 10 mg
J1459 - J1569, J1572 – J1599	Injection, immune globulin
J1700	Injection, hydrocortisone acetate, up to 25 mg
J1710	Injection, hydrocortisone sodium phosphate, up to 50 mg
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg
J2650	Injection, prednisolone acetate, up to 1 ml
J3299	Injection, triamcinolone acetonide (xipere), 1 mg
J3300	Injection, triamcinolone acetonide, preservative free, 1 mg
J3301	Injection, triamcinolone acetonide, not otherwise specified, 10 mg
J3302	Injection, triamcinolone diacetate, per 5 mg
J3303	Injection, triamcinolone hexacetonide, per 5 mg
J3304	Injection, triamcinolone acetonide, preservative-free, extended-release, microsphere formulation, 1 mg
J7509	Methylprednisolone oral, per 4 mg
J7510	Prednisolone oral, per 5 mg
J7512	Prednisone, immediate release or delayed release, oral, 1 mg
J8540	Dexamethasone, oral, 0.25 mg
J9333	Injection, rozanolixizumab-noli, 1 mg
ICD-10 codes covered if selection criteria are met:
G61.81	Chronic inflammatory demyelinating polyneuritis
G70.00 – G70.01	Myasthenia gravis
ICD-10 codes not covered for indications listed in the CPB:
L10.0	Pemphigus vulgaris
L10.2	Pemphigus foliaceous

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Background

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

• Vyvgart is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive.
• Vyvgart Hytrulo is indicated for the treatment of:
  
  
  • Generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive;
  • Adult patients with chronic inflammatory demyelinating polyneuropathy (CIDP).

Efgartigimod alfa-fcab is branded as Vyvgart (argenx US, Inc). Efgartigimod alfa-fcab is a neonatal Fc receptor blocker in which human IgG1 antibody fragment binds to the neonatal Fc receptor (FcRn) resulting in the reduction of circulating IgG. 

Vyvgart carries labeled warnings and precautions for risk of infection and hypersensitivity reactions, including rash, angioedema, and dyspnea. In a clinical trial, the most common infections observed were urinary tract infection (10% of Vyvgart-treated patients compared to 5% of placebo-treated patients) and respiratory tract infections (33% of Vyvgart-treated patients compared to 29% of placebo-treated patients). A higher frequency of patients who received Vyvgart compared to placebo were observed to have below normal levels for white blood cell counts (12% versus 5%, respectively), lymphocyte counts (28% versus 19%, respectively), and neutrophil counts (13% versus 6%, respectively). The majority of infections and hematologic abnormalities were mild to moderate in severity. Per the prescribing information, delay Vyvgart administration in patients with an active infection until the infection is resolved. During treatment with Vyvgart, monitor for clinical signs and symptoms of infections. If serious infection occurs, administer appropriate treatment and consider withholding Vyvgart until the infection has resolved. In clinical trials, hypersensitivity reactions were mild or moderate, occurred within one hour to three weeks of administration, and did not lead to treatment discontinuation.

Infusion-related reactions have been reported with Vyvgart in postmarketing experience. The most frequent symptoms and signs were hypertension, chills, shivering, and thoracic, abdominal, and back pain. Infusion-related reactions occurred during or within an hour of administration and led to infusion discontinuation.

The safety of immunization with live or live-attenuated vaccines and the response to immunization with any vaccine are unknown. Because Vyvgart causes a reduction in IgG levels, vaccination with live-attenuated or live vaccines is not recommended during treatment with Vyvgart. Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with Vyvgart.

The most common adverse reactions (10% or more) for patients with gMG treated with Vyvgart are respiratory tract infections, headache, and urinary tract infection.

Coformulation of efgartigimod alfa and hyaluronidase-qvfc (human recombinant) is branded as Vyvgart Hytrulo (argenx US, Inc). The addition of hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. This effect is transient and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

Labeled warnings and precautions for Vyvgart Hytrulo include increased risk of infection, hypersensitivity reactions (rash, angioedema, dyspnea, anaphylaxis), and infusion-related reactions (hypertension; chills; and thoracic, abdominal, and back pain). The most common adverse reactions (10% or more) in patients with generalized myasthenia gravis (gMG) treated with efgartigimod alfa-fcab were respiratory tract infections, headache, and urinary tract infection. Injection site reactions were common (15% or more) in patients with gMG and chronic inflammatory demyelinating polyneuropathy (CIDP) who were treated with Vyvgart Hytrulo.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare type of immune-mediated, inflammatory, peripheral nerve disorder that affects the myelin sheaths which leads to progressive muscle weakness, paresthesia, and difficulty with balance and coordination. CIDP can affect any age group and the onset of the disorder may begin during any decade of life; however, the average age of onset is 50 years. CIDP affects males twice as often as females. The prevalence of CIDP is estimated to be around 5 to 7 cases per 100,000 individuals (NORD, 2021a). 

In June 2024, the FDA approved Vyvgart Hytrulo for the treatment of CIDP in adults. FDA approval was based on the efficacy results from a two stage, multicenter study (NCT04281472) which 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 B, a total of 221 patients were randomized to receive weekly subcutaneous injections of Vyvgart Hytrulo (n=111) or placebo (n=110). Patients had a median age of 55 years (range: 20 to 82 years), a median time since CIDP diagnosis of 2.2 years, and median Inflammatory Neuropathy Cause and Treatment (INCAT) disability score of 3.0. Sixty-four percent were male and 65% were White, 30% Asian, and 1% African American. Stage B included 146 patients currently receiving standard-of-care therapy and 75 patients who had either not received prior treatment for CIDP or were not treated with standard-of-care therapy for at least 6 months before study entry. The primary endpoint was the time to clinical deterioration defined as a 1-point increase in adjusted INCAT (aINCAT) at two consecutive visits or a greater than 1-point increase in aINCAT at one visit. Patients who had clinical deterioration or completed week 48 in Stage B without clinical deterioration were withdrawn from the placebo-controlled portion of the study. The study stopped when 88 events of clinical deterioration occurred for the primary endpoint analysis. Part B of the study found that patients who received Vyvgart Hytrulo experienced a longer time to clinical deterioration compared to patients who received placebo, which was statistically significant as demonstrated by a hazard ratio of 0.394 [95% CI (0.253; 0.614) p<0.0001] (argenx, 2024b; FDA, 2024).

The rate of adverse reactions of Vyvgart Hytrulo in patients with CIDP was similar to those in patients with gMG who were treated with Vyvgart. 

Generalized Myasthenia Gravis (gMG)

Myasthenia gravis is a chronic autoimmune, neuromuscular disease that is characterized by weakness and fatigue of skeletal (voluntary) muscles that worsens after periods of activity and improves after periods of rest. The voluntary muscles affected can include those that are responsible for controlling the eyes, face, mouth, throat, limbs and respiratory muscles. In some affected individuals, the condition may be limited to certain eye muscles, which is often described as “ocular myasthenia". When myasthenia gravis affects multiple muscle groups throughout the body, it is called generalized myasthenia gravis (gMG). 

In myasthenia gravis, the immune system produces anti-acetylcholine receptor (AChR) antibodies that interfere with communication between nerves and muscles, resulting in muscle weakness and fatigue. Severe attacks of weakness, such as in myasthenia gravis crisis, can cause breathing and swallowing problems that can be life-threatening.

Myasthenia gravis is chronic but treatable disease, with many individuals achieving remission of symptoms. Initial symptomatic therapy consists of an acetylcholinesterase inhibitor such as oral pyridostigmine. Glucocorticoids and/or other immunosuppressive therapies are indicated for patients who remain significantly symptomatic on pyridostigmine (Bird, 2021).

On December 17, 2021, the U.S. FDA announced the approval of Vyvgart (efgartigimod) for the treatment of generalized myasthenia gravis (gMG) in adults who test positive for the anti-acetylcholine receptor (AChR) antibody. FDA approval was based on results from the global Phase 3 ADAPT trial (ClinicalTrials.gov NCT03669588).

In the ADAPT trial, Howard and colleagues (2021) aimed to assess the safety and efficacy of efgartigimod, a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalized myasthenia gravis (gMG). ADAPT was a randomized, double-blind, placebo-controlled, phase 3 trial conducted at 56 neuromuscular academic and community centers in 15 countries. Patients enrolled in the study met the following inclusion criteria: 18 years of age and older, Myasthenia Gravis Foundation of America (MGFA) clinical classification class II to IV, MG-Activities of Daily Living (MG-ADL) total score of ≥ 5 (>50% non-ocular), 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, and had IgG levels of at least 6 g/L. A total of 167 patients were randomized to receive either efgartigimod (10 mg/kg; 1200 mg for those weighing 120 kg or more) (n=84) or placebo (n=83), 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. 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. A statistically significant difference favoring efgartigimod was observed in the MG-ADL responder rate during the first treatment cycle [67.7% in the efgartigimod-treated group vs 29.7% in the placebo-treated group (p <0.0001)]. The secondary endpoint, measured using the Quantitative Myasthenia Gravis (QMG) score, was the comparison of the percentage of QMG responders during the first treatment cycle between both treatment groups in the AChR-Ab positive patients. A statistically significant difference favoring efgartigimod was observed in the QMG responder rate during the first treatment cycle [63.1% in the efgartigimod-treated group vs 14.1% in the placebo-treated group (p <0.0001)]. Out of 167 patients, 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. The authors concluded that efgartigimod was well tolerated and efficacious in patients with gMG. 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.

In June 2023, the FDA approved Vyvgart Hytrulo subcutaneous (SC) injectable for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive. Vyvgart Hytrulo consists of a combination of efgartigimod alfa, a human IgG1 antibody fragment marketed for intravenous use as Vyvgart, and recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s Enhanze® drug delivery technology to facilitate subcutaneous delivery of biologics. FDA approval is based on positive results from the Phase 3 ADAPT-SC study, which established the efficacy of Vyvgart Hytrulo by demonstrating a reduction in anti-AChR antibody levels comparable to intravenous Vyvgart in adult gMG patients. ADAPT-SC was a bridging study to the Phase 3 ADAPT study, which formed the basis for approval of intravenous Vyvgart in December 2021 (argenx, 2023). 

In the ADAPT-SC study, the primary endpoint of noninferiority was met (p< 0.0001) and Vyvgart Hytrulo demonstrated mean total IgG reduction of 66.4% from baseline at day 29, compared to 62.2% with Vyvgart. Additional key secondary endpoints were met, which were consistent with efficacy measures from the ADAPT study identifying the correlation between total IgG reduction and clinical benefit in gMG (argenx, 2023).

Vyvgart Hytrulo has a demonstrated safety profile, consistent with the ADAPT clinical trial with the exception of injection site reactions (ISRs), which were higher with Vyvgart Hytrulo. It was generally well-tolerated with ISRs being the most frequent adverse events. All ISRs, which are commonly observed with biologics administered subcutaneously, were mild to moderate, and resolved over time (argenx, 2023).

Pemphigus Vulgaris and Pemphigus Foliaceus

Maho-Vaillant et al (2022) noted that immunoglobulin G (IgG) levels are maintained by the IgG-recycling neonatal Fc-receptor (FcRn). Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are debilitating autoimmune disorders triggered by IgG auto-antibodies against mucosal and epidermal desmogleins. Recently, a phase-II clinical trial was completed in subjects with pemphigus using efgartigimod, an FcRn inhibitor, in combination with prednisone. Efgartigimod showed an early effect on disease activity and was well-tolerated.  In addition to the safety and effectiveness assessment, these studies presented an opportunity to gain more insights into the mechanism of disease, the mode of action of treatment, and potential for corticosteroid-sparing activity. In an open-label study, these researchers evaluated the impact of FcRn antagonism by efgartigimod on immunological parameters known to be directly involved in pemphigus pathology, such as cellular and serological responses. They examined total and antigen-specific IgG sub-class level kinetics during and after treatment, evaluated antigen-specific B-cell responses, followed T- and B-cell immunophenotypes, and analyzed how different immunophenotypes were linked to clinical response. Treatment resulted in reduction of total IgG as well as autoreactive IgG antibody levels. Surprisingly, unlike total IgG and vaccine- or natural-infection-elicited IgG, which returned to baseline levels after stopping efgartigimod treatment, auto-reactive antibody levels remained low in several study participants. Efgartigimod showed no effect on total leukocytes, neutrophils, monocytes, or lymphocytes in patients treated with extended efgartigimod therapy. Intriguingly, antigen-specific analyses revealed a loss of desmoglein-specific B cells in several subjects responding to efgartigimod, in line with prolonged reduction of pathogenic IgG levels. The authors concluded that efgartigimod treatment of patients with pemphigus improved their conditions and exerted an immunomodulatory effect beyond the blockade of IgG recycling. Moreover, these researchers stated that further studies in larger sample sizes and placebo control are needed to confirm these preliminary observations to establish long-term clinical responses in autoimmune diseases.

The authors stated that drawbacks of this secondary analysis included those associated with open-label studies, lack of placebo control, small sample size, and post-hoc analyses.  Peripheral blood mononuclear cells (PBMCs) collection was implemented in cohort 4 participants only following clinical observations from earlier cohorts and expert recommendations to expand understanding of efgartigimod’s impact on cellular and serological immunity. For few patients, PBMC samples with sufficient viability were available, allowing for longitudinal analyses.

Goebeler et al (2022) stated that PV and PF are potentially life-threatening autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. There is an unmet need for fast-acting drugs that enable patients to achieve early sustained remission with reduced corticosteroid reliance. In an open-label, single-arm, multi-center, phase-II feasibility trial, these investigators examined the effectiveness of efgartigimod in the treatment of patients with pemphigus. A total of 34 patients with mild-to-moderate PV or PF were enrolled in an open-label, phase II clinical trial. In sequential cohorts, efgartigimod was dosed at 10 or 25 mg/kg intravenously with various dosing frequencies, as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome. Adverse events (AEs) were mostly mild and were reported by 16 of 19 (84 %) patients receiving efgartigimod 10 mg/kg and 13 of 15 (87 %) patients receiving 25 mg/kg , with similar AE profiles between dose groups. A major decrease in serum total IgG and anti-desmoglein auto-antibodies was observed and correlated with improved Pemphigus Disease Area Index (PDAI) scores. Efgartigimod, as monotherapy or combined with prednisone, showed early disease control in 28 of 31 (90 %) patients after a median of 17 days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of prednisone 0.26 mg/kg/day (range of 0.06 to 0.48) led to complete clinical remission in 14 of 22 (64 %) patients within 2 to 41 weeks. The authors concluded that efgartigimod was well-tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus. These researchers stated that based on these data, a phase-III randomized controlled trial (RCT) was initiated to further examine the safety and effectiveness of efgartigimod in PV and PF.

The authors stated that drawbacks of this study included those associated with open‐label, single‐arm designs lacking a randomized, double‐blind control group, as well as the relatively short treatment periods and follow‐up. Furthermore, the varying use of prednisone among study participants and exclusion of severe manifestations of pemphigus from the study may limit the generalizability of these findings.

Zakrzewicz et al (2022) noted that PV is an autoimmune blistering disease of the epidermis, caused by autoantibodies against desmosomal proteins, mainly desmogleins 1 and 3, which induce an impairment of desmosomal adhesion and blister formation. Recent findings have shown that inhibition of IgG binding on the neonatal Fc receptor, FcRn, resulted in reduced autoantibody recycling and shortens their half-life, providing a valid therapeutic option for PV. These investigators examined the role of FcRn in human keratinocytes treated with antibodies isolated from PV patient or with recombinant anti-desmoglein-3 antibodies that induce pathogenic changes in desmosomes, such as loss of monolayer integrity, aberrant desmoglein-3 localization and degradation of desmoglein-3. They showed that blocking IgG binding on FcRn by efgartigimod stabilized the keratinocyte monolayer, whereas the loss of desmoglein-3 was not prevented by efgartigimod. These findings demonstrated that FcRn may play a direct role in the pathogenesis of pemphigus at the level of the autoantibody target cells, the epidermal keratinocytes. The authors concluded that these results suggested that in keratinocytes, FcRn may have functions different from its known function in IgG recycling; thus, stabilization of keratinocyte adhesion by FcRn blocking entities may provide a novel treatment paradigm for pemphigus.

Appendix

Myasthenia Gravis Foundation of America (MGFA) Clinical Classification

1. Class I: Any ocular muscle weakness; may have weakness of eye closure. All other muscle strength is normal.

2. Class II: Mild weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity.

   1. IIa. Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.
   2. IIb. Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of limb, axial muscles, or both.

3. Class III: Moderate weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity.

   1. IIIa. Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.
   2. IIIb. Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of limb, axial muscles, or both.

4. Class IV: Severe weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity.

   1. IVa. Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.
   2. IVb. Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of limb, axial muscles, or both.

5. Class V: Defined as intubation, with or without mechanical ventilation, except when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb.

Source: myasthenia.org

Myasthenia Gravis Activities of Daily Living Scale

The Myasthenia Gravis Activities of Daily Living Scale (MG-ADL) is an 8-item patient-reported outcome measure assessing myasthenia gravis (MG) symptoms and functional activities related to activities of daily living and producing a total score ranging from 0 to 24, where higher scores indicate greater severity of symptoms. The MG-ADL is composed of items related to patients’ assessment of functional disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb impairment (2 items).

Source: Canadian Agency for Drugs and Technologies in Health (2020)

The Myasthenia Gravis Composite

The Myasthenia Gravis Composite (MG Composite) is a 10-item tool that measures the signs and symptoms of myasthenia gravis (MG) based on physician examination and patient history. Scored items include ptosis, double vision, eye closure, talking, chewing, swallowing, breathing, neck flexion, shoulder abduction, and hip flexion. Each item is scored on an ordinal scale with four possible categories and weighted. The total score ranges from 0 to 50, with higher scores indicating more severe impairments. The MG Composite is composed of items originating from other scales (i.e., Quantitative Myasthenia Gravis [QMG], Manual Muscle Test [MMT], Myasthenia Gravis Activities of Daily Living [MG-ADL] scale).

Source: Canadian Agency for Drugs and Technologies in Health (2020)

The Manual Muscle Test

The MMT is a tool that evaluates the strength in 12 bilateral muscle groups and 6 ocular or axial (eg, neck flexors) muscles, that are usually affected in MG. Each muscle is scored from 0 (normal strength) to 4 (paralysis), and the total score is the sum of each muscle, where higher scores indicate more strength (less disease severity).

Source: Barnett et al (2018)

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References