Medical Policy

Policy Num:       M5.001.021
Policy Name:     Biological Treatments for Refractory Myasthenia Gravis
Policy ID:          [M5.001.021][Ac/MA/M/ P ][0.00.00]

Last Review:       June 25, 2024
Next Review:      June 20, 2025
 

Related Policies: 

M5.001.022 Ultomiris

Biological Treatments for Refractory Myasthenia Gravis

Summary

Description

Myasthenia gravis is an autoimmune neuromuscular disorder characterized by fluctuating motor weakness involving ocular, bulbar, limb, and/or respiratory muscles. The weakness is due to an antibody-mediated, immunologic attack directed at proteins in the postsynaptic membrane of the neuromuscular junction (acetylcholine receptors or receptor-associated proteins). Eighty to 90 percent of individuals with myasthenia gravis have autoantibodies against the acetylcholine receptor detectable in serum, and these antibodies are believed to play a central role in disease pathomechanism. Eculizumab (Soliris®) and ravulizumab-cwvz (Ultomiris®) are monoclonal antibodies that are presumed to exert a therapeutic effect in individuals with generalized myasthenia gravis through the reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. Efgartigimod alfa-fcab (Vyvgart®) is a human IgG1 antibody fragment that binds to the neonatal Fc receptor, resulting in the reduction of circulating IgG in individuals with generalized myasthenia gravis. Vygart Hytrulo is a coformulation of efgartigimod alfa and hyaluronidase (human recombinant) which can be administered subcutaneously. The addition of hyaluronidase increases the dispersion and absorption of co-administered drugs when administered subcutaneously. Rozanolixizumab-noli is a humanized IgG4 monoclonal antibody that binds to the neonatal Fc receptor resulting in the reduction of circulating IgG.

Summary of Evidence

For individuals with generalized myasthenia gravis who receive eculizumab, the evidence includes a single pivotal randomized controlled trial (RCT). Relevant outcomes are symptoms, quality of life, hospitalizations, and resource utilization. Results of the pivotal REGAIN trial reported a statistically significant difference in the primary endpoint favoring eculizumab in Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total scores compared with the placebo (least square mean difference of -1.9 points; 95% confidence interval [CI]: -3.3 to -0.6). A key secondary endpoint of change from baseline in the Quantitative Myasthenia Gravis (QMG) total score at week 26 also favored eculizumab compared with placebo (least square mean difference of -3.0 points; 95% CI: -4.6 to -1.3). Proportion of responders as defined by at least a 3-point reduction in MG‐ADL total score and at least a 5-point reduction in QMG total score from baseline to week 26 in eculizumab compared to placebo was 60% versus 40% and 45% versus 19%, respectively. An open-label extension of the pivotal trial provided additional evidence that showed that individuals who had received placebo during the REGAIN double-blind phase experienced rapid and sustained improvements during open-label eculizumab phase. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with generalized myasthenia gravis who receive ravulizumab, the evidence includes a single pivotal RCT. Relevant outcomes are symptoms, quality of life, hospitalizations, and resource utilization. Results of the pivotal CHAMPION MG trial reported a statistically significant difference in the primary endpoint favoring ravulizumab in MG-ADL total scores compared with the placebo (least square mean difference of -1.6 points, 95% CI: -2.6 to -0.7). A key secondary endpoint of change from baseline in the QMG total score at week 26 also favored ravulizumab compared with placebo (least square mean difference of -2.0 points, 95% CI: -3.2 to -0.8). Proportion of responders as defined by at least a 3-point reduction in MG‐ADL total score and at least a 5-point reduction in QMG total score from baseline to week 26 in eculizumab compared to placebo was 57% versus 34% and 30% versus 11%, respectively. Because of the relatively short follow-up, there is still considerable uncertainty about the long-term net benefits of ravulizumab compared with other treatment options. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with generalized myasthenia gravis who receive efgartigimod, the evidence includes 2 pivotal RCTs. Relevant outcomes are symptoms, quality of life, hospitalizations, and resource utilization. Two formulations are currently approved by the Food and Drug Administration (FDA): Vygart (efgartigimod alfa-fcab injection for intravenous infusion) and Vygart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc for subcutaneous use). Initial FDA approval of the intravenous formulation was based on a single RCT called ADAPT. Results of this trial reported a statistically significant difference in the primary endpoint favoring efgartigimod in MG-ADL responder rate compared with the placebo (67.7% versus 29.7%, respectively; p <.0001). MG-ADL responder was defined as a patient with a 2-point or greater reduction in the total MG-ADL score compared to the treatment cycle baseline for at least 4 consecutive weeks, with the first reduction occurring no later than 1 week after the last infusion of the cycle. A key secondary endpoint of responder based on QMG total score at week 26 also favored efgartigimod compared with placebo (63.1% versus 14.1%, respectively; p<.0001). QMG responder was defined as a patient who had a 3-point or greater reduction in the total QMG score compared to the treatment cycle baseline for at least 4 consecutive weeks, with the first reduction occurring no later than 1 week after the last infusion of the cycle. Subsequent approval of the subcutaneous formulation was based on the results of a bridging 10-week open-label randomized trial called ADAPT-SC. Results of this trial demonstrated pharmacodynamic non-inferiority based on the percent reduction in AChR-Ab levels from baseline to day 29. The least squares mean difference was 2.5% (95% CI: -7.45 to 2.41), which was below the upper limit of the confidence interval of 10%. Because of the relatively short follow-up, there is still considerable uncertainty about the long-term net benefits of efgartigimod compared with other treatment options. No major limitations in the study design and conduct were identified. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with generalized myasthenia gravis who receive rozanolixizumab, the evidence includes a single pivotal RCT. Relevant outcomes are symptoms, quality of life, hospitalizations, and resource utilization. Results of the pivotal RCT MycarinG reported a statistically significant difference in the primary endpoint favoring rozanolixizumab in MG-ADL total scores compared with the placebo (LS mean difference of -2.6 points for either dose of rozanolixizumab). A key secondary endpoint of change from baseline in the QMG total score at week 43 also favored rozanolixizumab [-5.4 points and -6.7 points in the rozanolixizumab-treated group at 7 mg/kg and 10 mg/kg dose level, respectively, compared with -1.9 points in the placebo-treated group (p<.001)]. Because of the relatively short follow-up, there is still considerable uncertainty about the long-term net benefits of rozanolixizumab compared with other treatment options. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Policy Statements

Eculizumab and Ravulizumab-cwvz - Initial Treatment

Eculizumab and ravulizumab-cwvz may be considered medically necessary for individuals with generalized myasthenia gravis (gMG) if they meet criteria 1 through 6:

1. 18 years of age or older.

2. Diagnosis of gMG with a class II to IV disease per the Myasthenia Gravis Foundation of America (MGFA) classification system (see Policy Guidelines).

3. Anti-acetylcholine receptor (AChR) antibody positive.

4. Impaired activities of daily living defined as a MG-Activities of Daily Living (MG-ADL) total score of ≥ 6.

5. Inadequate treatment response, intolerance, or contraindication to an acetylcholinesterase inhibitor (e.g., pyridostigmine, neostigmine) and at least ONE immunosuppressive therapy (e.g., azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, methotrexate, cyclophosphamide) either in combination or as monotherapy.

6. Not receiving dual therapy with another C5 complement inhibitor for gMG.

7. Vaccination against Neisseria meningitidis at least 2 weeks prior to initiation of therapy [unless treatment cannot be delayed].

8. Prescribing physician is enrolled in the appropriate Risk Evaluation and Mitigation Strategies (REMS) program.

Initial authorization period is for 6 months.

Eculizumab and Ravulizumab-cwvz - Continuation of Treatment

Incremental reauthorization for eculizumab and ravulizumab-cwvz may be considered medically necessary for individuals with gMG if they meet criteria 1 through 2:

1. Continues to meet the initial treatment criteria cited above.

2. Decrease of 2 points in MG-ADL total score from pre-treatment baseline value.

Reauthorization period is for 12 months.

Eculizumab and ravulizumab-cwvz are considered investigational for generalized myasthenia gravis when the above criteria are not met.

Efgartigimod alfa-fcab (intravenous) and efgartigimod alfa and hyaluronidase-gvfc (subcutaneous) - Initial Treatment

Efgartigimod alfa-fcab and efgartigimod alfa and hyaluronidase-gvfc may be considered medically necessary for individuals with gMG if they meet criteria 1 through 6:

1. 18 years of age or older.

2. Diagnosis of gMG with class II to IV disease per the MGFA classification system (see Policy Guidelines).

3. Anti-AChR antibody positive.

4. Impaired activities of daily living defined as a MG-ADL total score of ≥ 5.

5. Inadequate treatment response, intolerance, or contraindication to an acetylcholinesterase inhibitor (e.g., pyridostigmine, neostigmine) and at least ONE immunosuppressive therapy (e.g., azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, methotrexate, cyclophosphamide) either in combination or as monotherapy.

6. IgG levels ≥ 6 g/L.

Initial authorization period is for 6 months.

Efgartigimod alfa-fcab (intravenous) and efgartigimod alfa and hyaluronidase-gvfc (subcutaneous) - Continuation of Treatment

Incremental reauthorization for efgartigimod alfa-fcab and efgartigimod alfa and hyaluronidase-gvfc (subcutaneous) may be considered medically necessary for individuals with gMG if they meet criteria 1 through 2:

1. Continues to meet the initial treatment criteria cited above.

2. Decrease of 2 points in MG-ADL total score from pre-treatment baseline value.

Reauthorization period is for 12 months.

Efgartigimod alfa-fcab is considered investigational when the above criteria are not met.

Rozanolixizumab-noli - Initial Treatment

Rozanolixizumab-noli may be considered medically necessary for individuals with gMG if they meet criteria 1 through 6:

1. 18 years of a or older.

2. Diagnosis of gMG with class II to IVa disease per the MGFA classification system (see Policy Guidelines).

3. Anti-AChR antibody positive or anti-muscle-specific tyrosine kinase (MuSK) antibody positive.

4. Impaired activities of daily living defined as a MG-DLS total score of ≥ 3 and at least 3 points from non-ocular symptom(s).

5. Inadequate treatment response, intolerance, or contraindication to an acetylcholinesterase inhibitor (e.g., pyridostigmine, neostigmine) and at least ONE immunosuppressive therapy (e.g., azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, methotrexate, cyclophosphamide) either in combination or as monotherapy.

6. IgG levels ≥ 5.5 g/L.

Initial authorization period is for 6 months.

Rozanolixizumab-noli - Continuation of Treatment

Incremental reauthorization of rozanolixizumab-noli may be considered medically necessary for individuals with gMG if they meet criteria 1 through 2:

1. Individual continues to meet the initial treatment criteria cited above.

2. Decrease of 2 points in MG-ADL total score from pre-treatment baseline value.

Reauthorization period is for 12 months.

Rozanolixizumab-noli is considered investigational when the above criteria are not met.

Policy Guidelines

Eculizumab

Eculizumab is supplied in a 300 mg/30 mL single-dose vial. The recommended dose of eculizumab for adults with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive is 900 mg IV weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, than 1200 mg every 2 weeks thereafter. Administer eculizumab at the recommended dosage regimen time points, or within 2 days of these time points. Only administer as an IV infusion. Do not administer as an IV push or bolus injection. The IV infusion should be administered over 35 minutes in adults. If an adverse reaction occurs during eculizumab administration, the infusion may be slowed or stopped at the discretion of the clinician. If the infusion is slowed, the total infusion time should not exceed 2 hours in adults. Monitor the individual for at least 1 hour following completion of the infusion for signs or symptoms of an infusion-related reaction.

Ravulizumab-cwvz

Ravulizumab-cwvz is supplied in 300 mg/30 mL, 300 mg/3 mL, and 1100 mg/11 mL single-dose vials. The recommended IV dosage regimen of ravulizumab-cwvz for adults with gMG who are anti-AChR antibody positive is weight-based as follows:

• 40 to <60 kg: 2400 mg loading dose with a 3000 mg maintenance dose every 8 weeks;

• 60 to <100 kg: 2700 mg loading dose with a 3300 mg maintenance dose every 8 weeks;

• ≥100 kg: 3000 mg loading dose with a 3600 mg maintenance dose every 8 weeks.

The dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose); but subsequent doses should be administered according to the original schedule. Only administer as an IV infusion through a 0.2 or 0.22 micron filter. The subcutaneous dosage form is not indicated for generalized myasthenia gravis. If an adverse reaction occurs during ravulizumab-cwvz administration, the infusion may be slowed or stopped at the discretion of the clinician. Monitor the individual for at least 1 hour following completion of the infusion for signs or symptoms of an infusion-related reaction.

Efgartigimod alfa-fcab

Efgartigimod is supplied in a 400 mg/20 mL single-dose vial. The recommended dose of efgartigimod for adults with gMG who are anti-AChR antibody positive is 10 mg/kg given as an IV infusion over 1 hour once weekly for 4 weeks. In individuals weighing ≥120 kg, the recommended dose is 1200 mg per infusion. Providers should avoid administration of efgartigimod alfa-fcab to individuals with an active infection. 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, the drug may be given up to 3 days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed. Monitor individuals during administration and for 1 hour thereafter for clinical signs and symptoms of hypersensitivity reactions. If such a reaction occurs, discontinue therapy and institute appropriate supportive measures. Providers should evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with efgartigimod alfa-fcab.

Efgartigimod alfa and hyaluronidase-gvfc

Efgartigimod alfa and hyaluronidase-gvfc is supplied as a single-dose vial containing 1,008 mg efgartigimod alfa and 11,200 units hyaluronidase per 5.6 mL. Efgartigimod alfa and hyaluronidase-gvfc is intended for subcutaneous administration every 4 weeks by a healthcare professional. 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, the drug may be given up to 3 days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed. Monitor individuals during administration and for 30 minutes thereafter for clinical signs and symptoms of hypersensitivity reactions. If such a reaction occurs, discontinue therapy and institute appropriate supportive measures. Prescribers should evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with efgartigimod alfa and hyaluronidase-gvfc.

Rozanolixizumab-noli

Roznolixizumab-noli is supplied single-dose glass vial containing 280 mg/2 mL. The recommended dosage regimen of rozanolixizumab-noli is weight-based as follows:

• < 50 kg: 420 mg (3 mL) subcutaneous infusion once weekly every 6 weeks;

• 50 to < 100 kg: 560 mg (4 mL) subcutaneous infusion once weekly every 6 weeks;

• ≥ 100 kg: 840 mg (6 mL) subcutaneous infusion once weekly every 6 weeks.

Administer subsequent treatment cycles based on clinical evaluation. The safety of initiating subsequent cycles sooner than 63 days from the start of the previous treatment cycle has not been established. If a scheduled infusion is missed, the drug may be given up to 4 days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed.

It is recommended that individuals be monitored during administration and for 15 minutes thereafter for clinical signs and symptoms of hypersensitivity reactions, including angioedema and rash. If such a reaction occurs, discontinue therapy and institute appropriate supportive measures. In clinical trials, hypersensitivity reactions occurred up to 2 weeks post-administration.

It recommended that individuals are monitored for symptoms consistent with aseptic meningitis. In clinical trials, a total of three individuals developing drug-inducced aseptic meningitis, which lead to hospitalization and discontinuation of rozanolixizumab-noli.

Boxed Warning - Eculizumab and Ravulizumab-cwvz

There is a boxed warning regarding the potential for serious life-threatening and fatal meningococcal infections. The warning recommends that clinicians:

• Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in individuals with complement deficiencies;

• Immunize individuals with meningococcal vaccines at least 2 weeks prior to administering the first dose of eculizumab or ravulizumab-cwvz, unless the risks of delaying therapy outweighs the risk of developing a meningococcal infection;

• Monitor individuals for early signs of meningococcal infections and evaluate immediately if infection is suspected.

Advisory Committee on Immunization Practices Recommendations

Recent data suggest that meningococcal vaccines likely provide incomplete protection against invasive meningococcal disease in individuals receiving eculizumab. Experts believe this increased risk likely also applies to individuals receiving ravulizumab-cwvz. The Advisory Committee on Immunization Practices (ACIP) recommends both the meningococcal conjugate (MenACWY) and serogroup B meningococcal (MenB) vaccines for individuals receiving these complement inhibitors. Depending on the brand, the full series of MenB vaccine requires 2 or 3 doses, Administer a booster dose of MenACWY vaccine every 5 years, for the duration of complement inhibitor therapy. Administer a booster dose of MenB vaccine 1 year after series completion and then every 2 to 3 years thereafter, for the duration of therapy.

Risk Evaluation and Mitigation Strategies - Eculizumab and Ravulizumab-cwvz

The Food and Drug Administration (FDA) approved eculizumab and ravulizumab-cwvz with risk evaluation and mitigation strategies (REMS) in order to mitigate the occurrence and morbidity associated with meningococcal infections. Clinicians who prescribe eculizumab and ravulizumab-cwvz must:

• Become certified to prescribe the drug by reviewing the prescribing information, patient safety card, prescriber safety brochure, and patient safety brochure and enrolling in the REMS by completing a Prescriber Enrollment Form;

• Assess the individual's meningococcal vaccine status and immunize if necessary;

• Provide the individual with a prescription for a 2 week course of antibiotic prophylaxis if the drug must be initiated <2 weeks after the individual was immunized;

• Counsel the individual using the Patient Safety Card and Patient Safety Brochure and provide copies to the individual;

• Assess the individual for early signs of meningococcal infection and evaluate immediately, if infection is suspected;

• Discontinue the drug in individuals who are being treated for serious meningococcal infections;

• Revaccinate individuals according to the ACIP recommendations;

• Report cases of meningococcal infection, including the individual's clinical outcomes, to the manufacturer.

Myasthenia Gravis Foundation of America Clinical Classification

In 1997, the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America (MGFA) formed a task force to address the need for universally accepted classifications, grading systems, and analytic methods for management of individuals undergoing therapy and for use in therapeutic research trials. As a result, the MGFA Clinical Classification was created. This classification divides myasthenia gravis (MG) into 5 main classes and several subclasses, as follows:

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

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

IIa. Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.

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

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

IIIa. Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.

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

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

IVa. Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.

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

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 individual in class IVb.

Coding

See the Codes table for details.

RATIONALE

This evidence review was created in May 2022 with a search of the PubMed database. The most recent literature update was performed through Sep14, 2023.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Generalized Myasthenia Gravis

Clinical Context and Therapy Purpose

The purpose of eculizumab in adults who have gMG who are anti-acetylcholine receptor antibody positive is to provide a treatment option that is an alternative to existing therapeutic management for individuals with refractory disease.

The following PICO was used to select literature to inform this review.

Populations

The relevant population(s) of interest is adults with gMG who are anti-acetylcholine receptor antibody positive.

Interventions

The therapies being considered is eculizumab, ravulizumab-cwvz and efgartigimod.

Eculizumab and ravulizumab-cwvz are monoclonal antibodies that are presumed to exert a therapeutic effect in individuals with gMG through the reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. Rozanolixizumab-noli is also a humanized IgG4 monoclonal antibody that binds to the neonatal Fc receptor resulting in the reduction of circulating IgG. Efgartigimod alfa-fcab is a human IgG1 antibody fragment that binds to the neonatal Fc receptor, resulting in the reduction of circulating IgG in individuals with gMG.

Comparators

The following therapies are currently being used to make decisions about the treatment of gMG: acetylcholinesterase inhibitors, immunosuppressive agents, monoclonal antibodies, intravenous immunoglobulin/plasmapheresis, and thymectomy. Treatment is dependent upon response to therapy, setting (eg, preoperative), presence of myasthenic crisis, and etiology of myasthenia gravis.

Outcomes

The general outcomes of interest are symptoms, quality of life, hospitalizations, and resource utilization. Health outcome measures relevant to gMG in adults are summarized in Table 1.

Follow-up of months to years is of interest to monitor outcomes.

Table 1. Health Outcome Measures Relevant to Generalized Myasthenia Gravis in Adults^10,

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought;

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Population Reference No. 1

Eculizumab

Randomized Controlled Trials

Trial characteristics and results of the pivotal double-blind, placebo-controlled, phase 3 REGAIN trial are summarized in Tables 2 and 3, respectively.^11, The study met the primary efficacy endpoint. A statistically significant difference favoring eculizumab was observed in the mean change from baseline to week 26 in Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total scores [-4.2 points in the eculizumab-treated group compared with -2.3 points in the placebo-treated group (p=0.006)]. A key secondary endpoint of change from baseline in the Quantitative Myasthenia Gravis (QMG) total score at week 26 also favored eculizumab [-4.6 points in the eculizumab-treated group compared with -1.6 points in the placebo-treated group (p=.001)].^12, An open-label extension of the pivotal REGAIN trial reported data from a preplanned interim analysis that was based on a median duration of approximately 2 years of eculizumab therapy (N=117).^13, Results showed that individuals who had received placebo during the REGAIN double-blind phase experienced rapid and sustained improvements during the open-label eculizumab phase. Compared with the year before the REGAIN trial started (pre-study baseline), the myasthenia gravis exacerbation rate was reduced by 75.2% (pre-study, 102.4 exacerbations per 100 patient‐years; open‐label study, 25.4 exacerbations per 100 patient‐years; p <.0001).

Eculizumab was issued a boxed warning due to the life-threatening and fatal meningococcal infections that occurred in individuals treated with eculizumab and may become rapidly life-threatening or fatal if not recognized and treated early. The most frequently reported adverse reaction (≥10%) is musculoskeletal pain.^12,

Table 2. Summary of Pivotal RCT Characteristics

AChR: acetylcholine receptor; gMG: generalized myasthenia gravis; IV: intravenous; IVIG: intravenous immunoglobulin; MGFA: Myasthenia Gravis Foundation of America; MG-ADL: Myasthenia Gravis-Activities of Daily Living; RCT: randomized controlled trial.

Table 3. Summary of Pivotal RCT Results

The purpose of the study limitations table (Table 4) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following the table and provides the conclusions on the sufficiency of evidence supporting the position statement. The limited representations of African Americans, Asians, and Hispanics makes it challenging to reach conclusions about the efficacy of eculizumab in these racial groups. No major limitations in the study design and conduct were identified.

Table 4. Study Relevance Limitations

Sub-section Summary: Eculizumab

Results of the pivotal RCT REGAIN reported a statistically significant difference in the primary endpoint favoring eculizumab in MG-ADL total scores compared with the placebo (LS mean difference of -1.9 points; 95% CI: -3.3 to -0.6). A key secondary endpoint of change from baseline in the QMG total score at week 26 also favored eculizumab compared with placebo (LS mean difference of -3.0 points; 95% CI: -4.6 to -1.3). The proportion of responders as defined by at least a 3-point reduction in MG‐ADL total score and at least a 5-point reduction in QMG total score from baseline to week 26 in eculizumab compared to placebo was 60% versus 40% and 45% versus 19%, respectively. An open-label extension of the pivotal trial provided additional evidence that showed that individuals who had received placebo during the REGAIN double-blind phase experienced rapid and sustained improvements during the open-label eculizumab phase. Eculizumab was issued a boxed warning due to the life-threatening and fatal meningococcal infections that occurred in individuals treated with eculizumab and may become rapidly life-threatening or fatal if not recognized and treated early. The most frequently reported adverse reaction (≥10%) is musculoskeletal pain. The limited representations of African Americans, Asians, and Hispanics makes it challenging to reach conclusions about the efficacy of eculizumab in these racial groups. No major limitations in the study design and conduct were identified.

For individuals with generalized myasthenia gravis who receive eculizumab, the evidence includes a single pivotal randomized controlled trial (RCT). Relevant outcomes are symptoms, quality of life, hospitalizations, and resource utilization. Results of the pivotal REGAIN trial reported a statistically significant difference in the primary endpoint favoring eculizumab in Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total scores compared with the placebo (least square mean difference of -1.9 points; 95% confidence interval [CI]: -3.3 to -0.6). A key secondary endpoint of change from baseline in the Quantitative Myasthenia Gravis (QMG) total score at week 26 also favored eculizumab compared with placebo (least square mean difference of -3.0 points; 95% CI: -4.6 to -1.3). Proportion of responders as defined by at least a 3-point reduction in MG‐ADL total score and at least a 5-point reduction in QMG total score from baseline to week 26 in eculizumab compared to placebo was 60% versus 40% and 45% versus 19%, respectively. An open-label extension of the pivotal trial provided additional evidence that showed that individuals who had received placebo during the REGAIN double-blind phase experienced rapid and sustained improvements during open-label eculizumab phase. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Ravulizumab

Randomized Controlled Trials

Trial characteristics and results of the pivotal double-blind, placebo-controlled, phase 3 CHAMPION MG trial are summarized in Tables 5 and 6, respectively.^15, The study met the primary efficacy endpoint. A statistically significant difference favoring ravulizumab was observed in the mean change from baseline to week 26 in MG-ADL total scores [-3.1 points in the ravulizumab-treated group compared with -1.4 points in the placebo-treated group (p=.001)]. A key secondary endpoint of change from baseline in the QMG total score at week 26 also favored ravulizumab [-2.8 points in the ravulizumab-treated group compared with -0.8 points in the placebo-treated group (p=.001)].^16, Responder analysis also favored the ravulizumab treated arm compared to placebo.

Ravulizumab was issued a boxed warning due to the life-threatening and fatal meningococcal infections that occurred in individuals treated with eculizumab and may become rapidly life-threatening or fatal if not recognized and treated early. The most frequently reported adverse reactions (≥10%) were upper respiratory tract infection and headache.^16,

Table 5. Summary of Pivotal RCT Characteristics

Table 6. Summary of Pivotal RCT Results

The purpose of the study limitations table (Table 7) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following the table and provides the conclusions on the sufficiency of evidence supporting the position statement. The limited representations of African Americans, Asians, and Hispanics makes it challenging to reach conclusions about the efficacy of ravulizumab in these racial groups. Because of relatively short follow-up, there is still considerable uncertainty about the long-term net benefits of ravulizumab compared with other treatment options. No major limitations in the study design and conduct were identified.

Table 7. Study Relevance Limitations

Sub-section Summary: Ravulizumab-cwvz

Results of the pivotal RCT CHAMPION MG reported a statistically significant difference in the primary endpoint favoring ravulizumab in MG-ADL total scores compared with the placebo (LS mean difference of -1.6 points; 95% CI: -2.6 to -0.7). A key secondary endpoint of change from baseline in the QMG total score at week 26 also favored ravulizumab compared with placebo (LS mean difference of -2.0 points; 95% CI: -3.2 to -0.8). The proportion of responders as defined by at least a 3-point reduction in MG‐ADL total score and at least a 5-point reduction in QMG total score from baseline to week 26 in eculizumab compared to placebo was 57% versus 34% and 30% versus 11%, respectively. Ravulizumab was issued a boxed warning due to the life-threatening and fatal meningococcal infections that occurred in individuals treated with ravulizumab and may become rapidly life-threatening or fatal if not recognized and treated early. The most frequently reported adverse reactions (≥10%) were upper respiratory tract infection and headache. The limited representations of African Americans, Asians, and Hispanics makes it challenging to reach conclusions about the efficacy of ravulizumab in these racial groups. Because of relatively short follow-up, there is still considerable uncertainty about the long-term net benefits of ravulizumab compared with other treatment options. No major limitations in the study design and conduct were identified.

For individuals with generalized myasthenia gravis who receive ravulizumab, the evidence includes a single pivotal RCT. Relevant outcomes are symptoms, quality of life, hospitalizations, and resource utilization. Results of the pivotal CHAMPION MG trial reported a statistically significant difference in the primary endpoint favoring ravulizumab in MG-ADL total scores compared with the placebo (least square mean difference of -1.6 points, 95% CI: -2.6 to -0.7). A key secondary endpoint of change from baseline in the QMG total score at week 26 also favored ravulizumab compared with placebo (least square mean difference of -2.0 points, 95% CI: -3.2 to -0.8). Proportion of responders as defined by at least a 3-point reduction in MG‐ADL total score and at least a 5-point reduction in QMG total score from baseline to week 26 in eculizumab compared to placebo was 57% versus 34% and 30% versus 11%, respectively. Because of the relatively short follow-up, there is still considerable uncertainty about the long-term net benefits of ravulizumab compared with other treatment options. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3

Efgartigimod

Two formulations are currently approved by the FDA- Vygart (efgartigimod alfa-fcab injection for intravenous infusion) and Vygart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc for subcutaneous use). The US FDA approval of the intravenous formulation was based on a 26-week double-blind placebo-controlled randomized trial called ADAPT, while the approval for the subcutaneous formulation was based on the results of a bridging 10-week open-label randomized trial called ADAPT-SC. These are summarized next.

Randomized Controlled Trials

Trial characteristics and results of the pivotal trialsare summarized in Tables 8 and 9, respectively.^17,18, ADAPT was a double-blind, placebo-controlled, phase 3 trial. While it enrolled individuals regardless of anti-AChR antibody status, the primary endpoint and subsequent approval of efgartigimod by the FDA was only for individuals who were AChR-Ab positive. The study met the primary efficacy endpoint. A statistically significant difference favoring efgartigimod was observed in the MG-ADL responder rate [67.7% in the efgartigimod -treated group vs 29.7% in the placebo-treated group (p <.0001)]. A key secondary endpoint of comparison of the proportion of QMG responders between the 2 treatment groups also favored efgartigimod [63.1% in the efgartigimod-treated group vs 14.1% in the placebo-treated group (p <.0001)]. The most frequently reported adverse reactions (≥10%) were respiratory tract infections, headache, and urinary tract infection.

ADAPT-SC was a randomized open-label parallel-group trial with the objective to demonstrate pharmacodynamic non-inferiority of the subcutaneous formulation to that of the intravenous formulation. It also enrolled individuals regardless of anti-AChR antibody status. The noninferiority evaluation was based on the percent reduction from baseline in AChR-Ab levels at day 29 (ie, week 4) using an noninferiority margin of 10% meaning that when the lower limit of the 95% confidence interval for the difference is above the margin of -10, the subcutaneous formulation will be considered noninferior to the IV formulation.^19, The least squares mean difference in the percent change from baseline of AChR-Ab levels was 2.5% (95% CI: -7.45 to 2.41), which is below the upper limit of the confidence interval of 10%.^20, Additionally, the 90% CIs for the geometric mean ratios of AChR-Ab reduction at day 29 and AUEC_0-4w (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.^21,

Table 8. Summary of Pivotal RCT Characteristics

Table 9. Summary of Pivotal RCT Results

The purpose of the study limitations table (Table 10) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following the table and provides the conclusions on the sufficiency of evidence supporting the position statement. The limited representations of African Americans, Asians, and Hispanics makes it challenging to reach conclusions about the efficacy of efgartigimod in these racial groups. Because of the relatively short follow-up, there is still considerable uncertainty about the long-term net benefits of efgartigimod compared with other treatment options. No major limitations in the study design and conduct were identified.

Table 10. Study Relevance Limitations

Sub-section Summary: Efgartigimod

Two formulations are currently approved by the FDA: Vygart (efgartigimod alfa-fcab injection for intravenous infusion) and Vygart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc for subcutaneous use). Initial FDA approval of the intravenous formulation was based on a single RCT called ADAPT. Results of this trial reported a statistically significant difference in the primary endpoint favoring efgartigimod in MG-ADL responder rate compared with the placebo (67.7% versus 29.7%, respectively; p <.0001). A key secondary endpoint of responder based on QMG total score at week 26 also favored efgartigimod compared with placebo (63.1% versus 14.1%, respectively; p <.0001). The most frequently reported adverse reactions (≥10%) were respiratory tract infections, headache, and urinary tract infection. Subsequent approval of the subcutaneous formulation was based on the results of a bridging 10-week open-label randomized trial called ADAPT-SC. Results of this trial demonstrated pharmacodynamic non-inferiority based on the percent reduction in AChR-Ab levels from baseline to day 29. The least squares mean difference was 2.5% (95% CI: -7.45 to 2.41), which was below the upper limit of the confidence interval of 10%. The limited representations of African Americans, Asians, and Hispanics in the ADAPT trial make it challenging to reach conclusions about the efficacy of efgartigimod in these racial groups. Because of the relatively short follow-up, there is still considerable uncertainty about the long-term net benefits of efgartigimod compared with other treatment options. No major limitations in the study design and conduct were identified.

For individuals with generalized myasthenia gravis who receive efgartigimod, the evidence includes 2 pivotal RCTs. Relevant outcomes are symptoms, quality of life, hospitalizations, and resource utilization. Two formulations are currently approved by the Food and Drug Administration (FDA): Vygart (efgartigimod alfa-fcab injection for intravenous infusion) and Vygart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc for subcutaneous use). Initial FDA approval of the intravenous formulation was based on a single RCT called ADAPT. Results of this trial reported a statistically significant difference in the primary endpoint favoring efgartigimod in MG-ADL responder rate compared with the placebo (67.7% versus 29.7%, respectively; p <.0001). MG-ADL responder was defined as a patient with a 2-point or greater reduction in the total MG-ADL score compared to the treatment cycle baseline for at least 4 consecutive weeks, with the first reduction occurring no later than 1 week after the last infusion of the cycle. A key secondary endpoint of responder based on QMG total score at week 26 also favored efgartigimod compared with placebo (63.1% versus 14.1%, respectively; p<.0001). QMG responder was defined as a patient who had a 3-point or greater reduction in the total QMG score compared to the treatment cycle baseline for at least 4 consecutive weeks, with the first reduction occurring no later than 1 week after the last infusion of the cycle. Subsequent approval of the subcutaneous formulation was based on the results of a bridging 10-week open-label randomized trial called ADAPT-SC. Results of this trial demonstrated pharmacodynamic non-inferiority based on the percent reduction in AChR-Ab levels from baseline to day 29. The least squares mean difference was 2.5% (95% CI: -7.45 to 2.41), which was below the upper limit of the confidence interval of 10%. Because of the relatively short follow-up, there is still considerable uncertainty about the long-term net benefits of efgartigimod compared with other treatment options. No major limitations in the study design and conduct were identified. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4

Rozanolixizumab

Randomized Controlled Trials

Trial characteristics and results of the pivotal double-blind, placebo-controlled, phase 3 MycarinG trial are summarized in Tables 11 and 12, respectively. The study met the primary efficacy endpoint. A statistically significant difference favoring rozanolixizumab was observed in the mean change from baseline to day 43 in MG-ADL total scores [-3.4 points in the rozanolixizumab-treated group either doses compared with -0.8 points in the placebo-treated group (p<.001)]. A key secondary endpoint of change from baseline in the QMG total score at week 43 also favored rozanolixizumab [-5.4 points and -6.7 points in the rozanolixizumab-treated group at 7 mg/kg and 10 mg/kg dose level, respectively, compared with -1.9 points in the placebo-treated group (p<.001)]. The most common adverse reactions (≥10%) were headache, infections, diarrhea, pyrexia, hypersensitivity reactions, and nausea. Serious events of aseptic meningitis were reported. As per the label, symptoms for meningitis should be monitored and diagnostic workup and treatment should be initiated according to the standard of care.^22,

Table 11. Summary of Pivotal RCT Characteristics

Table 13. Study Relevance Limitations

Sub-section Summary: Rozanolixizumab

Results of the pivotal RCT MycarinG reported a statistically significant difference in the primary endpoint favoring rozanolixizumab in MG-ADL total scores compared with the placebo (LS mean difference of -2.6 points for either doses of rozanolixizumab). A key secondary endpoint of change from baseline in the QMG total score at week 43 also favored rozanolixizumab [-5.4 points and -6.7 points in the rozanolixizumab-treated group at 7 mg/kg and 10 mg/kg dose level, respectively compared with -1.9 points in the placebo-treated group (p<.001)]. The most common adverse reactions (≥10%) were headache, infections, diarrhea, pyrexia, hypersensitivity reactions, and nausea. Serious events of aseptic meningitis were reported. The limited representations of African Americans, Asians, and Hispanics makes it challenging to reach conclusions about the efficacy of rozanolixizumab in these racial groups. Because of relatively short follow-up, there is still considerable uncertainty about the long-term net benefits of rozanolixizumab compared with other treatment options. No major limitations in the study design and conduct were identified.

For individuals with generalized myasthenia gravis who receive rozanolixizumab, the evidence includes a single pivotal RCT. Relevant outcomes are symptoms, quality of life, hospitalizations, and resource utilization. Results of the pivotal RCT MycarinG reported a statistically significant difference in the primary endpoint favoring rozanolixizumab in MG-ADL total scores compared with the placebo (LS mean difference of -2.6 points for either dose of rozanolixizumab). A key secondary endpoint of change from baseline in the QMG total score at week 43 also favored rozanolixizumab [-5.4 points and -6.7 points in the rozanolixizumab-treated group at 7 mg/kg and 10 mg/kg dose level, respectively, compared with -1.9 points in the placebo-treated group (p<.001)]. Because of the relatively short follow-up, there is still considerable uncertainty about the long-term net benefits of rozanolixizumab compared with other treatment options. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

DOSAGE/ADMINISTRATION

REQUIRED MEDICAL INFORMATION

Text

EXCLUSION CRITERIA

Text

BENEFIT APPLICATION

Triple-S Coverage Drugs Determination

Triple-S Salud will consider the following agents as covered agents: 

• Eculizumab
• Ravulizumab-cwvz
• Efgartigimod alfa-fcab (intravenous) or efgartigimod alfa and hyaluronidase-qvfc(subcutaneous) for shared FDA approved conditions. 

Based on literature Review, Rozanolixizumab-noli, efectiveness is the lowest on class.  Studies have demonstrated an effectiveness of 11.79% at the primary efficacy endpoint wich was the percentage of Myasthenia Gravis–Specific Activities of Daily Living Scale (MG-ADL) responders in a 26-week cycles and the mean change in MG-ADL from baseline to Week 26.   Based on this information coverage for Rozanolixizumab-noli, 1 mg will be evaluated based on an exeption process that may take into consideration : 

A. Trial and failure of all of the following: Eculizumab, Ravulizumab-cwvz, Efgartigimod alfa-fcab (intravenous) or efgartigimod alfa and hyaluronidase-qvfc(subcutaneous) resulting in minimal
clinical response to therapy

OR

B. History of intolerance or adverse event to all of the following: Eculizumab, Ravulizumab-cwvz, Efgartigimod alfa-fcab (intravenous) or efgartigimod alfa and hyaluronidase-qvfc(subcutaneous).

AND

C. Anti muscle specific tyriosine kinase antibody status

OTHER CRITERIA

Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determination (NCD), Local Coverage Determinations (LCDs), and Local Coverage Articles (LCAs) may exist and compliance with these policies is required where applicable. They can be found at: http://www.cms.gov/medicare-coverage-database/search/advanced-search.aspx. Additional indications may be covered at the discretion of the health plan

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Myasthenia Gravis Foundation of America

In 2021, an international consensus guidance for the management of myasthenia gravis was published.^24, This guidance contained recommendations for the use of eculizumab including:

• "Eculizumab should be considered in the treatment of severe, refractory, acetylcholine receptor antibody-positive generalized myasthenia gravis.

• The role of eculizumab in the treatment of myasthenia gravis is likely to evolve over time; until further data become available to allow comparisons of cost and efficacy with other treatments, eculizumab should be considered after trials of other immunotherapies have been unsuccessful in meeting treatment goals.

• Future research should include assessment of the duration of eculizumab therapy necessary to achieve and maintain treatment goals, its efficacy in other myasthenia gravis populations, and in other stages of disease."

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force (USPSTF) recommendations for the treatment of generalized myasthenia gravis have been identified.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 14.

Table 14. Summary of Key Trials

References

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22. Prescribing label: Rystiggo (rozanolixizumab-noli) injection, for subcutaneous use. Available at https://www.ucb-usa.com/RYSTIGGO-prescribing-information.pdf. Accessed on September 20, 2023.
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Codes

Policy History