Coverage Policy Manual
Policy #: 2016013
Category: Pharmacy
Initiated: May 2016
Last Review: October 2022
  C5 Complement Inhibitors [(Eculizumab (e.g., Soliris®) and Ravulizumab-cwvz (e.g., Ultomiris™)]

Description:
Eculizumab, a recombinant humanized monoclonal IgG2/4 antibody selectively inhibits the terminal portion of the complement system by specifically binding to the terminal C5, which acts at a late stage in the complement cascade.  Inhibition of the complement cascade at this point, preserves the normal, disease-preventing functions of proximal complement system while impeding the properties of C5 that promote inflammation and cell destruction. As a recombinant humanized monoclonal antibody that binds to complement protein C5, eculizmab effectlively inhibits enzymatic cleavage and blocks formation of the terminal complement complex, preventing red cell lysis in paroxysmal nocturnal hemoglobinuria (PNH) and complement-mediated thrombotic microangiopathy in atypical hemolytic uremic syndrome (aHUS).
 
On March 16, 2007, Eculizumab (e.g., Soliris®; Alexion Pharmaceuticals, Inc. Cheshire, CT), a humanized monoclonal antibody that binds to the human C5 complement protein, received accelerated approval by the U.S. Food and Drug Administration for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis.  Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem disorder clinically characterized by chronic complement-mediated hemolysis, thrombosis, and bone marrow failure. Thrombosis, the major cause of death in PNH, is observed in approximately 40% of patients. The symptoms associated with this disorder, including fatigue, pain, esophageal spasm, and erectile dysfunction, are often severe and disabling.
 
On Sep 23, 2011 the U.S. Food and Drug Administration (FDA) approved Eculizumab (e.g., Soliris®) for the treatment of all pediatric and adult patients with atypical hemolytic uremic syndrome (aHUS).  Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. Typical (acquired) HUS is triggered by infectious agents such as strains of E. coli (Stx-E. coli) that produce powerful Shiga-like exotoxins, whereas atypical HUS (aHUS) can be genetic, acquired, or idiopathic (of unknown cause). Onset of atypical HUS ranges from prenatal to adulthood. Individuals with genetic atypical HUS frequently experience relapse even after complete recovery following the presenting episode. Sixty percent of genetic aHUS progresses to end-stage renal disease (ESRD).
 
In I0/2017, the FDA approved Eculizumab for the treatment of adult patients with generalized Myasthenia Gravis (gMg) who are anti-acetylcholine receptor (AChR) antibody positive.  MG is a common disorder of neuromuscular transmission characterized by a variable combination of weakness in ocular, bulbar, limb, and respiratory muscles.  Autoantibodies to the acetylcholine receptor is present in 73% - 88% of patients with gMG. In the REGAIN study (NCT01997229), Eculizumab produced meaningful improvements in ADL’s, muscle strength, functional ability and quality of life in those patients with AchR refractory gMG.
 
Eculizumab was also approved for neuromyelitis optic spectrum disorder (NMOSD) in adult patients who are anti-aquapoin-4 (AQP4-IgG) antibody positive on June 27, 2019.  NMOSD is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of the cases are associated with AQP4-IgG and complement-mediated damage to the central nervous system.
 
Ravulizumab-cwvz (e.g., Ultomiris™)
Ravulizumab is a humanized monoclonal antibody to complement component C5, engineered from eculizumab, (e.g., Soliris).  It specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal compliment complex [C5b-9]) and preventing the generation of the terminal complement C5b9.  Ravulizumab inhibits terminal complement-mediated intravascular hemolysis in patient with paroxysmal nocturnal hemoglobinuria (PNH).
 
Complement inhibitors have black box warnings for serious meningococcal infections. Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors and meningococcal infection may become rapidly life-threating or fatal if not recognized and treated early. Individuals should be immunized with meningococcal vaccines at least 2 weeks prior to initiation of therapy unless the risks of delaying therapy outweigh the risk of developing a meningococcal infection. The FDA has required the manufacturers to develop comprehensive risk management programs that include the enrollment of prescribers in the Soliris REMS or Ultomiris REMS Programs respectively. Additional information and forms for individuals, prescribers, and pharmacists may be found on the manufacturer’s websites: http://www.solirisrems.com or http://www.ultomirisrems.com.
 
On December 21, 2018 the FDA granted both priority review and Orphan Drug designation for Ravulizumab for the indication of PNH.   
 
On Oct 18, 2019 Ravulizumab was FDA approval for treating adults and pediatric patients one month or older for atypical hemolytic uremic syndrome (aHus)
 
On April 27, 2022, the Food and Drug Administration approved ravulizumab (e.g., Ultomiris) for the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive.
 
Coding
Effective 7/1/2019 there is a specific HCPCS for Ravulizumab-cwvz.
C9052 - Injection, ravulizumab-cwvz, 10 mg
J1303-Injection, ravulizumab-cwvz, 10 mg-effective 10/1/2019

Policy/
Coverage:
Effective April 01, 2018, prior approval is required for Eculizumab (e.g., Soliris).
 
Effective February 2019 Prior Approval is required for Ravulizumab (e.g., Ultomiris)
 
The use of ravulizumab on-body delivery system for subcutaneous administration is not covered under the medical benefit. Please check member’s pharmacy benefit for coverage of ravulizumab on-body delivery system.
 
The use of ravulizumab intravenous (IV) injection is covered under the medical benefit.
 
The use of these drugs requires documentation of direct physician (MD/DO) involvement in the ordering and evaluation as well as a signature in the medical records submitted for prior approval.
 
The Step Therapy Medication Act is applicable to fully insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The l196251aw is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, Tyson, or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
 
Effective October 19, 2022
 
RAVULIZUMAB-cwvz (e.g., Ultomiris)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Ravulizumab IV solution for injection meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for all following indications when ALL criteria are met:  
 
A. Paroxysmal Nocturnal Hemoglobinuria (PNH)
  
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
1. The individual is an adult, >18 yrs or a pediatric patient 1 month of age and older; AND
2. Individual has diagnosis of PNH as documented by flow cytometry, including the presence of:
a. >10% of PNH type III red cells, AND
b. >40% glycosylphosphatidylinositol-anchored proteins (GPI-AP)-deficient polymorphonuclear cells (PMNs) (Parker, 2016); AND
3. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab OR provide 2 weeks of antibacterial drug prophylaxis if Ravulizumab must be initiated immediately and vaccines are administered less than 2 weeks before starting therapy (FDA, 2021); AND
4. Either of the following criteria are met (Parker, 2016):
a. The individual has: Hemoglobin that is less than or equal to 7 g/dl, or the individual has symptoms of anemia, and the hemoglobin is less than or equal to 9 g/dl; OR
b. Documented history of a major adverse vascular event (MAVE) from thromboembolism; AND
5. Will not be used in combination with another complement inhibitor used to treat PNH; AND
6. Must be dosed in accordance with the FDA label unless otherwise specified.
 
CONTINUED APPROVAL for 1 year:
 
1. Has met all the initial criteria; AND
2. Documentation demonstrating a positive clinical response from baseline:
a. Increased of stabilization of hemoglobin levels; AND
b. Reduction in transfusions; AND
c. Improvement in hemolysis (e.g., normalization or decrease of LDH levels); AND
3. Improvement in fatigue and quality of life.
 
Dosing and Administration
Note: Refer to package insert for details surrounding transitions from eculizumab, scheduling and most recent dosing recommendations.
 
IV administration: The recommended dosing for adults and pediatric patients with PNH consists of a loading dose followed by maintenance dosing beginning 2 weeks following the loading dose.
  
                  Body weight range                   Loading dose                      Maintenance dose
                 >5kg - <10 kg                                 600 mg                           300 mg every 4wks
                 >10kg - <20 kg                              600 mg                            600 mg every 4wks
                 >20 kg - <30 kg                             900 mg                            2,100 mg every 8 weeks
                 >30kg - <40kg                             1,200 mg                           2,700 mg every 8 weeks
     >40kg - <60kg                             2,400 mg                           3,000 mg every 8 weeks
                 >60kg - >100kg                           2,700 mg                           3,300 mg every 8 weeks
                 >100kg                                       3,000 mg                           3,600 mg every 8 weeks
 
Ravulizumab IV solution for injection is available in 3 vial strengths and sizes:
 
300 mg/30mL (10mg/mL) single dose vial
300 mg/3mL (100mg/mL) single dose vial
1,100 mg/11mL (100mg/mL) single dose vial
 
Ravulizumab IV solution for injection should be administered by a healthcare professional.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
B. Atypical Hemolytic Syndrome (aHUS)
 
INITIAL APPROVAL STANDARD REVIEW for 6 weeks:
 
1. The individual is an adult, >18 yrs or a pediatric patient 1 month of age and older; AND
2. The individual has a diagnosis of aHUS supported by the absence of Shiga toxin-producing E. coli infection (FDA, 2021); AND
3. Thrombotic thrombocytopenic purpura (TTP) has been ruled out (for example, normal ADAMTS 13 activity and no evidence of an ADAMTS 13 inhibitor), or if TTP cannot be ruled out by laboratory and clinical evaluation, a trial of plasma exchange did not result in clinical improvement (George, NEJM 2014; Scully, 2017) AND
4. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab OR provide 2 weeks of antibacterial drug prophylaxis if Ravulizumab must be initiated immediately and vaccines are administered less than 2 weeks before starting therapy (FDA, 2021); AND
5. Will not be used in combination with another complement inhibitor or other biologic agent used to treat aHUS; AND
6. Will not be used concomitantly with plasma exchange; AND
7. Must be dosed in accordance with the FDA label unless otherwise specified.
 
CONTINUED APPROVAL for no more than 1 year:
 
1. Has met all the initial criteria; AND
2. Individual has documentation demonstrating a positive clinical response from baseline:
a. Increased platelet count from pretreatment baseline; AND
b. Reduction in plasma exchanges, reduction in dialysis, increased platelet count; AND
c. Improvement in hemolysis (e.g., normalization or decrease in LDH levels); AND
d. Stabilization/improvement in serum creatinine/eGFR from pretreatment baseline
 
REINITIATION of ravulizumab for aHUS:
Requests for reinitiation of ravulizumab in aHUS may be approved if the following criteria are met (Fakhouri 2017):
 
1. The individual met the initiation criteria above; AND
2.   Documentation is provided that the individual experienced a relapse after discontinuation of therapy as defined by:
a. Reduction in platelet count to less than 150,000/mm3 or greater than 25% from baseline; OR
b. Mechanical hemolysis (having 2 or more features of hemoglobin less than 10 g/dL, lactate dehydrogenase greater than 2 times upper limit of normal, undetectable haptoglobin, or presence of schistocytes on smear); OR
c. Acute kidney injury with serum creatinine increase greater than 15% from baseline levels.
 
 
Dosing and Administration
Note: Refer to package insert for details surrounding transitions from eculizumab, scheduling and most recent dosing recommendations.
 
IV administration: The recommended dosing for adults and pediatric patients with aHUS consists of a loading dose followed by maintenance dosing beginning 2 weeks following the loading dose.
  
                  Body wt range                          Loading dose                      Maintenance dose
                 >5kg – <10 kg                                 600 mg                            300 mg every 4wks
                 >10kg - <20 kg                                600 mg                            600 mg every 4wks
                 >20 kg - <30 kg                               900 mg                            2,100 mg every 8 weeks
                 >30kg - <40kg                                 1,200 mg                         2,700 mg every 8 weeks
     >40kg - <60kg                                 2,400 mg                         3,000 mg every 8 weeks
                 >60kg - >100kg                               2,700 mg                         3,300 mg every 8 weeks
                 >100kg                                           3,000 mg                         3,600 mg every 8 weeks
 
Ravulizumab IV solution for injection is available in 3 vial strengths and sizes:
 
300 mg/30mL (10mg/mL) single dose vial
300 mg/3mL (100mg/mL) single dose vial
1,100 mg/11mL (100mg/mL) single dose vial
 
Ravulizumab IV solution for injection should be administered by a healthcare professional.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
C. Generalized Myasthenia Gravis (gMG)
  
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
1. Individual is >18 years of age (FDA, 2022), AND
2. Individual has a diagnosis of refractory chronic gMG classified as Class II to IV per the MG Foundation of America Clinical Classification confirmed by a neurologist with specialization in the treatment of gMG with Class II-IV disease. (FDA, 2022); AND
3. The individual has a Myasthenia Gravis-Specific Activities of Daily Living (MG-ADL) total score of greater than or equal to 6 at initiation. (FDA, 2022); AND
4. The individual has evidence of a positive serologic test for AChR antibodies (FDA, 2022); AND
5. Individual has had an inadequate treatment response to an acetylcholinesterase inhibitor and at least TWO immunosuppressive therapies either in combination or as monotherapy, such as (Howard, 2017; Liu, 2010):
· Azathioprine
· Cyclosporine
· Mycophenolate mofetil
· Tacrolimus
· Methotrexate
· Cyclophosphamide
· Glucocorticoids; AND
6. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of ravulizumab OR is provided 2 weeks of antibacterial drug prophylaxis if ravulizumab must be initiated immediately and vaccines are administered less than 2 weeks before starting therapy (FDA, 2022); AND
7. The individual has had an inadequate response to chronic intravenous immunoglobulin (IVIG) or plasmapheresis/plasma exchange over 12 months (Howard, 2017; Liu, 2010); AND
8. Individual will not be receiving IVIG or any another biologic agent (ravulizumab, rituximab, inebilizumab, satralizumab efgartigimod) for gMG in combination with this product.  (FDA, 2022); AND
9. Must be dosed in accordance with the FDA label unless otherwise specified.
 
CONTINUED APPROVAL for 1 year:
Continuation of ravulizumab following initial approval for the treatment of gMG meets primary coverage criteria when:
 
1. All the above requirements have previously been met; AND
2. The individual has evidence of benefit of the following:
a. clinically significant improvement in the signs and symptoms of myasthenia gravis as documented in the medical record by a neurologist with specialization in the treatment of myasthenia gravis (i.e., Individual has had fewer relapses while on ravulizumab); AND
b. Improvement and/or maintenance of at least a 2-point improvement (reduction in score) in the MG-ADL score from pre-treatment baseline; AND
c. IVIG or any other biologic agent for gMG is not being used in combination with ravulizumab.
 
Dosing and Administration
Note: Refer to package insert for details surrounding transitions from eculizumab, scheduling, and most recent dosing recommendations.
 
The recommended dosing for adults and pediatric patients with gMG consists of a loading dose followed by maintenance dosing by IV infusion beginning 2 weeks following the loading dose.
 
         Body wt range              Loading dose                     Maintenance dose
        >40kg to <60 kg            2,400 mg x 1 dose             3,000 mg every 8 wks  
        >60kg to <100kg           2,700 mg x 1 dose             3,300 mg every 8 wks
        >100kg                         3,000 mg x 1 dose             3,600 mg every 8 wks
 
Ravulizumab IV solution for injection is available in 3 vial strengths and sizes:
 
300 mg/30mL (10mg/mL) single dose vial
300 mg/3mL (100mg/mL) single dose vial
1,100 mg/11mL (100mg/mL) single dose vial
 
Ravulizumab IV solution for injection should be administered by a healthcare professional.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Ravulizumab, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes including the following:
1. antibody-mediated rejection in organ transplantation; OR
2. antineutrophil cytoplasmic autoantibody (ANCA) vasculitis; OR
3. antiphospholipid antibody syndrome (APS); OR
4. dense deposit disease or C3 nephropathy; OR
5. hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia; OR
6. hemolytic cold agglutinin disease; OR
7. nonexudative (dry) age-related macular degeneration; OR
8. Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS); OR
9. systemic lupus erythematosus (SLE); OR
10. thrombotic thrombocytopenic purpura (TTP); OR
11. concomitant use with IVIG
 
For members with contracts without primary coverage criteria, ravulizumab, for any indication or circumstance not described above, is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
ECULIZUMAB (e.g., Soliris)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Eculizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for all following indications when ALL criteria are met:
 
A. Paroxysmal Nocturnal Hemoglobinuria (PNH)
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
1. Individual as diagnosis of PNH as documented by flow cytometry, including the presence of
a. >10% of PNH type III red cells (Hillmen, 2006); AND
b. > 40% Glycosylphosphatidylinositol-anchored proteins (GPI-AP)-deficient polymorphonuclear cells (PMNs); AND
2. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab (unless the clinical record documents that the risks of delaying eculizumab outweigh the risk of meningococcal infection) (FDA, 2020); AND
3. Either of the following criteria (a) OR (b) are met (Parker, 2016):
a. The individual has: Hemoglobin that is less than or equal to 7 g/dl, or the individual has symptoms of anemia, and the hemoglobin is less than or equal to 9 g/dl (Hillmen, 2006); OR
b. Documented history of a major adverse vascular event (MAVE) from thromboembolism (Parker, 2016); AND
4. Will not be used in combination with another complement inhibitor used to treat PNH; AND
5. Must be dosed in accordance with the FDA label unless otherwise specified.
 
CONTINUED APPROVAL for no more than 1 year:
 
1. Has met all the initial criteria; AND
2. Documentation demonstrating a positive clinical response from baseline:
a. Increased of stabilization of hemoglobin levels; AND
b. Reduction in transfusions; AND
c. Improvement in hemolysis (e.g., normalization or decrease of LDH levels); AND
3. Improvement in fatigue and quality of life.
 
Dosing and Administration
 
The recommended dosing for adults >18 years of age:
· 600 mg every 7 days for the first 4weeks, followed by
· 900 mg for the 5th dose 7 days later, then every 14 days thereafter.
 
Eculizumab is available as a single dose vial that is 300 mg/30mL and should be administered by a healthcare professional.  
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
B. Atypical Hemolytic Uremic Syndrome (aHUS)
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
1. The individual has a diagnosis of aHUS supported by the absence of Shiga toxin-producing E. coli infection (FDA, 2020); AND
2. Thrombotic thrombocytopenic purpura (TTP) has been ruled out (for example, normal ADAMTS 13 activity and no evidence of an ADAMTS 13 inhibitor), or if TTP cannot be ruled out by laboratory and clinical evaluation, a trial of plasma exchange did not result in clinical improvement (George, 2014; Scully, 2017) AND
3. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab (unless the clinical record documents that the risks of delaying eculizumab outweigh the risk of meningococcal infection) (FDA, 2020)
4. Will not be used in combination with another complement inhibitor used to treat aHUS.
5. Must be dosed in accordance with the FDA label unless otherwise specified.
 
CONTINUED APPROVAL for no more than 1 year:
 
1. Has met all the initial criteria; AND
2. Individual has documentation demonstrating a positive clinical response from baseline:
a. Increased platelet count from pretreatment baseline; AND
b. Reduction in plasma exchanges, reduction in dialysis, increased platelet count; AND
c. Improvement in hemolysis (e.g., normalization or decrease in LDH levels); AND
d. Stabilization/improvement in serum creatinine/eGFR from pretreatment baseline
 
REINITIATION of eculizumab for aHUS:
 
Requests for reinitiation of eculizumab in aHUS may be approved if the following criteria are met (Fakhouri 2017):
 
1. The individual met the initiation criteria above; AND
2. Documentation is provided that the individual experienced a relapse after discontinuation of therapy as defined by:
a. Reduction in platelet count to less than 150,000/mm3 or greater than 25% from baseline; OR
b. Mechanical hemolysis (having 2 or more features of hemoglobin less than 10 g/dL, lactate dehydrogenase greater than 2 times upper limit of normal, undetectable haptoglobin, or presence of schistocytes on smear); OR
c. Acute kidney injury with serum creatinine increase greater than 15% from baseline levels.
 
Dosing and Administration
 
The recommended dose for adults >18 years of age:
· 900 mg weekly for the first 4 weeks, followed by
· 1200 mg for the 5th dose 1 week later, then every 2 weeks thereafter
 
For patients less than 18 years of age, administer eculizumab, (e.g., Soliris) based upon body weight, according to the following schedule:
 
Body weight range                      Loading dose                         Maintenance dose
5kg to <10 kg                         300mg weekly x 1 dose              300 mg at wk 2; then every 3 wks
10kg to <20kg                        600mg weekly x 1 dose              300 mg at wk 2; then every 2 wks   
20kg to <30kg                        600mg weekly x 2 doses            600 mg at wk 3; then every 2 wks   
30kg to <40kg                        600 mg weekly x 2 doses           900 mg at wk 3; then every 2 wks
>40kg                                     900 mg weekly x 4 doses          1200 mg at wk 5; then every 2 wks
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
C. Myasthenia Gravis (gMG)
  
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
1. Individual is >18 years of age (FDA, 2020), AND
2. Individual has a diagnosis of refractory chronic gMG classified as Class II to IV per the MG Foundation of America Clinical Classification confirmed by a neurologist with specialization in the treatment of gMG with Class II-IV disease. (FDA, 2022); AND
3. The individual has a Myasthenia Gravis-Specific Activities of Daily Living (MG-ADL) total score of greater than or equal to 6 at initiation. (FDA, 2022); AND
4. The individual has evidence of a positive serologic test for AChR antibodies (FDA, 2022); AND
5. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab OR is provided 2 weeks of antibacterial drug prophylaxis if ravulizumab must be initiated immediately and vaccines are administered less than 2 weeks before starting therapy (FDA, 2021); AND
6. Individual has had an inadequate treatment response to an acetylcholinesterase inhibitor and at least TWO immunosuppressive therapies either in combination or as monotherapy, such as (Howard, 2017; Liu, 2010):
· Azathioprine
· Cyclosporine
· Mycophenolate mofetil
· Tacrolimus
· Methotrexate
· Cyclophosphamide
· Glucocorticoids; AND
7. The individual has had an inadequate response to chronic intravenous immunoglobulin (IVIG) or plasmapheresis/plasma exchange over 12 months.  (Howard, 2017; Liu, 2010); AND
8. Individual will not be receiving IVIG or any another biologic agent (ravulizumab, rituximab, inebilizumab, satralizumab efgartigimod) for gMG in combination with this product.  (FDA, 2020); AND
9. Must be dosed in accordance with the FDA label unless otherwise specified.
 
CONTINUED APPROVAL for 1 year:
 
Continuation of eculizumab following initial approval for the treatment of gMG
 
1. All the above requirements have previously been met; AND
2. The individual has evidence of benefit of the following:
a. clinically significant improvement in the signs and symptoms of myasthenia gravis as documented in the medical record by a neurologist with specialization in the treatment of myasthenia gravis (i.e., Individual has had fewer relapses while on eculizumab); AND
b. Improvement and/or maintenance of at least a 2-point improvement (reduction in score) in the MG-ADL score from pre-treatment baseline AND
c. IVIG or any other biologic agent for gMG is not being used in combination with eculizumab.
 
Dosing and Administration
 
The recommended dose for adults >18 years of age:
· 900 mg weekly for the first 4 weeks, followed by
· 1200 mg for the 5th dose 1 week later, then every 2 weeks thereafter.
 
Eculizumab is available as a single dose vial that is 300 mg/30mL and should be administered by a healthcare professional.  
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
D. Neuromyelitis optica spectrum disorder (NMOSD)
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
1. The individual is > 18 yrs of age (FDA, 2020); AND
2. A diagnosis of Neuromyelitis Optica or NMOSD (Pittock, 2019) as identified by documentation of at least one core clinical characteristic as follows:
a. Optic neuritis
b. Acute myelitis
c. Area postrema syndrome – episode of otherwise unexplained hiccups or nausea and vomiting
d. Acute brainstem syndrome
e. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions
f. Symptomatic cerebral syndrome with NMOSD-typical brain lesions; AND
3. Evidence of AQP4-IgG – Seropositive status (preferably cell-based assay) (Pittock, 2019); AND
4. A history of at least 2 relapses during the previous 12 months or 3 relapses during the previous 24 months, at least one of which had occurred within the previous 12 months (Pittock, 2019); AND
5. The use of concurrent corticosteroids limited to 20 mg per day (Pittock, 2019); AND
6. Will be ordered by or in consultation with a neurologist; AND
7. Will not have been treated with rituximab or mitoxantrone within 3 months or IVIG within 3 weeks prior to screening (Pittock, 2019); AND
8. Will not be given concurrently with other biologics or IVIG or plasma exchange (FDA, 2020); AND
9. Evidence of failure of, contraindications to, or intolerance of rituximab treatment (Mealy, 2014); AND
10. Evidence of failure of, contraindication to, or intolerance of ineilizumab (Uplizna) or satralizumab (Ensprying); AND
11. The individual is not receiving eculizumab in combination with any of the following:
a. Disease modifying therapies for the treatment of multiple sclerosis [e.g., Gilenya (fingolimod), Tecfidera (dimethyl fumarate), Ocrevus (ocrelizumab),
b. Anti-IL6 therapy [e.g., Actemra (tocilizumab), Enspryng (satralizumab]
c. B-cell depletion therapy [e.g., rituximab, Uplizna (inebilizumb-cdon)]
d. Other biologic agents
12. Must be dosed in accordance with the FDA label unless otherwise specified.
 
CONTINUED APPROVAL for 1 year:
 
Continuation of eculizumab following initial approval for the treatment of neuromyelitis optica spectrum disorder
1. All the above requirements have been met.
2. There is no evidence of relapse of the NMOSD.
 
Dosing and Administration
 
The recommended dose for adults > 18 years is as follows:
· 900 mg weekly for the first 4 weeks, followed by
· 1200 mg for the 5th dose 1 week later, then every 2 weeks thereafter.
 
Eculizumab is available as a single dose vial that is 300 mg/30mL and should be administered by a healthcare professional.  
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Eculizumab for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes including the following:
1. antibody-mediated rejection in organ transplantation
2. antineutrophil cytoplasmic autoantibody (ANCA) vasculitis
3. antiphospholipid antibody syndrome (APS)
4. dense deposit disease or C3 nephropathy
5. hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia
6.  hemolytic cold agglutinin disease
7.  nonexudative (dry) age-related macular degeneration
8. Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS)
9. systemic lupus erythematosus (SLE)
10. thrombotic thrombocytopenic purpura (TTP)
11. concomitant use with IVIG
 
For members with contracts without primary coverage criteria, eculizumab for any other indication or circumstance not described above, is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to June 1, 2022, are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
 
Effective June 29, 2022 - October 18, 2022
 
ECULIZUMAB (e.g., Soliris®)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
1. Paroxysmal Nocturnal Hemoglobinuria
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
Eculizumab meets primary coverage criteria for the treatment of an individual with documented paroxysmal nocturnal hemoglobinuria (PNH) when ALL of the following criteria are met:
 
  1. PNH as documented by flow cytometry, including the presence of >10% of:
        1. PNH type III red cells (Hillmen, 2006); AND
        2.  > 40% Glycosylphosphatidylinositol-anchored proteins (GPI-AP)-deficient polymorphonuclear cells (PMNs); AND
 
2. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab (unless the clinical record documents that the risks of delaying eculizumab outweigh the risk of meningococcal infection) (FDA, 2020); AND
3. Either of the following criteria (a) OR (b) are met:
        1. The individual has: Hemoglobin that is less than or equal to 7 g/dl, or the individual has symptoms of anemia, and the hemoglobin is less than or equal to 9 g/dl (Hillmen, 2006); OR
        2. Documented history of a major adverse vascular event (MAVE) from thromboembolism (Parker, 2016)
 
4. Participation in the SOLIRIS REMS program (FDA, 2020)
 
Dosing per FDA Guidelines
 
For >18 years of age:
    • 600 mg every 7 days for the first 4weeks, followed by
    • 900 mg for the 5th dose 7 days later, then every 14 days thereafter.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
CONTINUED APPROVAL for 1 year:
Continuation of eculizumab following an initial 6-month trial for the treatment of PNH meets member benefit certificate primary coverage criteria when there is documentation of clinical improvement after the initial trial (for example, increased Hgb and Hct count or laboratory evidence of reduced hemolysis).
 
2. Atypical Hemolytic Uremic Syndrome (aHUS)
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
Eculizumab meets primary coverage criteria for the treatment of atypical hemolytic uremic syndrome (aHUS) when the following criteria are met:
 
    1. The diagnosis of aHUS is supported by the absence of Shiga toxin-producing E. coli infection (FDA, 2020); AND
    2. Thrombotic thrombocytopenic purpura (TTP) has been ruled out (for example, normal ADAMTS 13 activity and no evidence of an ADAMTS 13 inhibitor), or if TTP cannot be ruled out by laboratory and clinical evaluation, a trial of plasma exchange did not result in clinical improvement (George, 2014; Scully, 2017) AND
    3. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab (unless the clinical record documents that the risks of delaying eculizumab outweigh the risk of meningococcal infection) (FDA, 2020)
    4. Participation in the SOLIRIS REMS program (FDA, 2020)
 
Dosing per FDA Guidelines
 
For >18 years of age:
    • 900 mg weekly for the first 4 weeks, followed by
    • 1200 mg for the 5th dose 1 week later, then every 2 weeks thereafter
 
For patients less than 18 years of age, administer Soliris based upon body weight, according to the following schedule:
 
Body wt range                          Loading dose                         Maintenance dose
>40kg                                    900 mg weekly x 4 doses         1200 mg at wk 5; then every 2 wks
 30kg to <40kg                      600 mg weekly x 2 doses           900 mg at wk 3; then every 2 wks
 20kg to <30kg                      600mg weekly x 2 doses            600 mg at wk 3; then every 2 wks   
 10kg to <20kg                      600mg weekly x 1 dose              300 mg at wk 2; then every 2 wks   
  5kg to <10 kg                      300mg weekly x 1 dose              300 mg at wk 2; then every 3 wks
 
CONTINUED APPROVAL for 1 year:
Continuation of eculizumab following an initial 6- week month trial for the treatment of aHUS meets member benefit certificate primary coverage criteria when there is documentation of clinical improvement after the initial trial (for example, increased platelet count or laboratory evidence of reduced hemolysis).
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
3. Myasthenia Gravis (gMG) – (effective June 2019)
 
The use of eculizumab in the treatment of refractory chronic generalized myasthenia gravis (gMG) meets primary coverage criteria when ALL of the following criteria are met:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
    1. Individual is >18 years of age (FDA, 2020), AND
    2. A diagnosis of refractory chronic generalized Myasthenia Gravis is confirmed by a neurologist with specialization in the treatment of myasthenia gravis with Class II-IV disease (per MGFA criteria), AND member has a myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score of 6 or greater at initiation (FDA, 2020), AND
    3. There is confirmation of a positive AChR-ab (anti-acetylcholine receptor antibodies) (Howard, 2017) test and a negative MuSK (muscle-specific tyrosine kinase) antibody test. (If member is MuSK positive, then Eculizumab is only available if the member has failed or intolerant of rituximab and meets ALL of the other criteria) (Sanders, 2016) AND
    4. The individual is on stable dose of MG therapy prior to screening, that included acetylcholinesterase (AChE) inhibitors, steroids, or non-steroidal immunosuppressive therapies (NSISTs), either in combination or alone (Howard, 2021) AND
    5. The individual has received meningococcal vaccine 2 weeks prior to the initiation of eculizumab (FDA, 2020), AND
    6. The individual has documentation of inadequate response to treatment, with at least two disease modifying agents (e.g.  glucocorticoids, azathioprine, cyclosporine, methotrexate, mycophenolate, tacrolimus) over at least 12 months (Howard, 2017; Liu, 2010); AND/OR
    7. The individual has had an inadequate response to chronic intravenous immunoglobulin (IVIG) or plasmapheresis/plasma exchange over 12 months.  (Howard, 2017; Liu, 2010) AND
    8. Individual will not be receiving IVIG in combination with this product.  (FDA, 2020) AND
    9. Participation in the SOLIRIS REMS program (FDA, 2020)
 
CONTINUED APPROVAL for 1 year:
Continuation of therapy for generalized myasthenia gravis meets primary coverage criteria when:
 
    1. All the above requirements have previously been met
    2. The individual has evidence of benefit of the following:
        1. clinically significant improvement in the signs and symptoms of myasthenia gravis as documented in the medical record by a neurologist with specialization in the treatment of myasthenia gravis.
        2. improvement in the pretreatment baseline MG-ADL score and/or maintenance of score over time.
        3. IVIG is not being used concomitantly with eculizumab
 
Dosing per FDA labeling
 
    • 900 mg weekly for the first 4 weeks, followed by
    • 1200 mg for the 5th dose 1 week later, then every 2 weeks thereafter.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
4. Neuromyelitis optica spectrum disorder (NMOSD) – effective June 27, 2019
 
Eculizumab meets primary coverage criteria for the treatment of an individual with neuromyelitis optica spectrum disorder when ALL of the following are met:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
    1. The individual is > 18 yrs of age (FDA, 2020) AND
    2. A diagnosis of Neuromyelitis Optica or NMOSD (Pittock, 2019) as identified by documentation of at least one core clinical characteristic as follows:
        1. Optic neuritis
        2. Acute myelitis
        3. Area postrema syndrome – episode of otherwise unexplained hiccups or nausea and vomiting
        4. Acute brainstem syndrome
        5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions
        6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions AND
 
3.  Evidence of AQP4-IgG – Seropositive status (preferably cell-based assay) (Pittock, 2019) AND
4. A history of at least 2 relapses during the previous 12 months or 3 relapses during the previous 24 months, at least one of which had occurred within the previous 12 months (Pittock, 2019) AND
5. The use of concurrent corticosteroids limited to 20 mg per day (Pittock, 2019) AND
6. Will be ordered by or in consultation with a neurologist AND
7. Participation in the SOLIRIS REMS program (FDA, 2020) AND
8. Will not have been treated with rituximab or mitoxantrone within 3 months or IVIg within 3 weeks prior to screening (Pittock, 2019) AND
9. Will not be given concomitantly with other biologics or IVIG (FDA, 2020) AND
10. Evidence of failure of, contraindications to, or intolerance of rituximab treatment (Mealy, 2014) AND
11. Evidence of failure of, contraindication to, or intolerance of ineilizumab (Uplizna) or satralizumab (Ensprying).
 
CONTINUED APPROVAL for 1 year:
Continuation of therapy for neuromyelitis optica spectrum disorder meets primary coverage criteria when:
    1. All of the above requirements have been met.
    2. There is no evidence of relapse of the NMOSD.
 
Dosing per FDA labeling
 
    • 900 mg weekly for the first 4 weeks, followed by
    • 1200 mg for the 5th dose 1 week later, then every 2 weeks thereafter.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Eculizumab does not meet primary coverage criteria and is not covered for any other indication including but not limited to the following:
 
    1. antibody-mediated rejection in organ transplantation
    2. antineutrophil cytoplasmic autoantibody (ANCA) vasculitis
    3. antiphospholipid antibody syndrome (APS)
    4. dense deposit disease or C3 nephropathy
    5. hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia
    6.  hemolytic cold agglutinin disease
    7.  nonexudative (dry) age-related macular degeneration
    8. Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS)
    9. systemic lupus erythematosus (SLE)
    10. thrombotic thrombocytopenic purpura (TTP)
    11. concomitant use with IVIG
 
For members with contracts without primary coverage criteria, eculizumab for any other indication including, but not limited to, the indications listed above as not covered, is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
RAVULIZUMAB-cwvz (e.g., Ultomiris™)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
1. Paroxysmal Nocturnal Hemoglobinuria (PNH)
 
Ravulizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness with paroxysmal nocturnal hemoglobinuria (PNH) when ALL of the following is met:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
    1. PNH as documented by flow cytometry, including the presence of >10% of:
        1. PNH type III red cells, AND
        2. >40% glycosylphosphatidylinositol-anchored proteins (GPI-AP)-deficient polymorphonuclear cells (PMNs) (Parker, 2016) AND
2. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab OR provide 2 weeks of antibacterial drug prophylaxis if Ravulizumab must be initiated immediately and vaccines are administered less than 2 weeks before starting therapy (FDA, 2021); AND
3. Either of the following criteria are met (Parker, 2016):
        1. The individual has: Hemoglobin that is less than or equal to 7 g/dl, or the individual has symptoms of anemia, and the hemoglobin is less than or equal to 9 g/dl; OR
        2. Documented history of a major adverse vascular event (MAVE) from thromboembolism
4. Participation in the ULTOMIRIS REMS program (FDA, 2021)
 
CONTINUED APPROVAL for 1 year:
 
    1. Has met all of the initial criteria.
    2.  Documentation demonstrating a positive clinical response from baseline:
        1. Increased of stabilization of hemoglobin levels
        2. Reduction in transfusions
    3. Improvement in fatigue and quality of life.
 
Dosing and Administration per FDA Guidelines
 
The recommended dosing regimen for adult patients > 18 years with PNH consists of a loading dose followed by maintenance dosing administered by intravenous infusion.
 
    1. Starting 2 weeks after the loading dose, begin maintenance doses once every 8 weeks.  
    2. The schedule is allowed to occasionally vary within 7 days of the scheduled infusion day, (except for the first maintenance dose), but the subsequent dose should be administered according to the original schedule.   
    3. Switching from Eculizumab to Ravulizumab:
    4. 2 weeks after the last dose of Eculizumab, give the loading dose of Ravulizumab.
    5. 2 weeks after the loading dose of Ravulizumab, give maintenance dose, then once every 8 weeks after.
 
                  Body wt range                          Loading dose                      Maintenance dose
                  >40kg - <60kg                             2,400 mg                               3,000 mg
                  >60kg - >100kg                           2,700 mg                               3,300 mg
                 >100kg                                        3,000 mg                               3,600 mg
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
2. Atypical Hemolytic Syndrome (aHUS) – Effective April 6, 2020
 
Ravulizumab meets primary coverage criteria for the treatment of atypical hemolytic uremic syndrome (aHUS) when ALL of the following criteria are met:
 
INITIAL APPROVAL STANDARD REVIEW for 6 weeks:
 
    1. The diagnosis of aHUS is supported by the absence of Shiga toxin-producing E. coli infection (FDA, 2021); AND
    2. Thrombotic thrombocytopenic purpura (TTP) has been ruled out (for example, normal ADAMTS 13 activity and no evidence of an ADAMTS 13 inhibitor), or if TTP cannot be ruled out by laboratory and clinical evaluation, a trial of plasma exchange did not result in clinical improvement (George, NEJM 2014; Scully, 2017) AND
    3. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab OR provide 2 weeks of antibacterial drug prophylaxis if Ravulizumab must be initiated immediately and vaccines are administered less than 2 weeks before starting therapy (FDA, 2021); AND
    4. Participation in the ULTOMIRIS REMS program (FDA, 2021)
 
CONTINUED APPROVAL for 1 year:
Continuation of ravulizumab following an initial 6-week trial for the treatment of aHUS meets member benefit certificate primary coverage criteria when there is documentation of clinical improvement after the initial trial (for example, increased platelet count or laboratory evidence of reduced hemolysis).
 
Dosing and Administration
 
For adults and pediatric patients with aHUS, administer Ravulizumab based upon body weight, according to the following schedule:
 
         Body wt range              Loading dose                     Maintenance dose
        >5kg to <10 kg              600 mg x 1 dose                300 mg every 4 wks
        >10kg to <20kg             600 mg x 1 dose                600 mg every 4 wks
         >20kg to <30kg              900 mg x1 dose                 2,100 mg every 8 wks   
         >30kg to <40kg             1,200 mg x 1 dose              2,700 mg every 8 wks  
         >40kg to <60 kg            2,400 mg x 1 dose              3,000 mg every 8 wks  
        >60kg to <100kg           2,700 mg x 1 dose              3,300 mg every 8 wks
          >100kg                         3,000 mg x 1 dose               3,600 mg every 8 wks
 
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
2. Generalized Myasthenia Gravis (gMG) – Effective April 27, 2022
 
Ravulizumab meets primary coverage criteria for the treatment of generalized myasthenia gravis (gMG) when ALL of the following criteria are met:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
    1. Diagnosed with MG at least 6 months (180 days) prior to the date of screening visit. (FDA, 2022)
    2. MG Foundation of America Clinical Classification Class II to IV at screening (FDA, 2022)
    3. MG-ADL profile must be greater than or equal to 6 at screening. (FDA, 2022).
    4. Diagnosis of MG must be confirmed by a neurologist with specialization in the treatmetn of MG with Class II-IV disease. AND
    5. Evidence of a positive serologic test for anti-acetylcholine receptor (AChR) antibodies (FDA, 2022); AND
    6. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab OR provide 2 weeks of antibacterial drug prophylaxis if Ravulizumab must be initiated immediately and vaccines are administered less than 2 weeks before starting therapy (FDA, 2021); AND
    7. The individual has documentation of inadequate response to treatment, with at least two disease modifying agents (e.g.  glucocorticoids, azathioprine, cyclosporine, methotrexate, mycophenolate, tacrolimus) over at least 12 months (Howard, 2017; Liu, 2010); AND/OR
    8. The individual has had an inadequate response to chronic intravenous immunoglobulin (IVIG) or plasmapheresis/plasma exchange over 12 months.  (Howard, 2017; Liu, 2010) AND
    9. Individual will not be receiving IVIG in combination with this product.  (FDA, 2020) AND
    10. Participation in the ULTOMIRIS REMS program (FDA, 2022)
 
CONTINUED APPROVAL for 1 year:
Continuation of ravulizumab following initial approval for the treatment of gMG meets member benefit certificate primary coverage criteria when there is documentation of clinical improvement.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Ravulizumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other condition than including but not limited to:
    1. antibody-mediated rejection in organ transplantation
    2. antineutrophil cytoplasmic autoantibody (ANCA) vasculitis
    3. antiphospholipid antibody syndrome (APS)
    4. dense deposit disease or C3 nephropathy
    5. hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia
    6. hemolytic cold agglutinin disease
    7. nonexudative (dry) age-related macular degeneration
    8. Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS)
    9. systemic lupus erythematosus (SLE)
    10. thrombotic thrombocytopenic purpura (TTP)
    11. concomitant use with IVIG
 
For members with contracts without primary coverage criteria, Ravulizumab is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective June 1, 2022 to June 28, 2022
 
ECULIZUMAB (e.g., Soliris®)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
1. Paroxysmal Nocturnal Hemoglobinuria
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
Eculizumab meets primary coverage criteria for the treatment of an individual with documented paroxysmal nocturnal hemoglobinuria (PNH) when ALL of the following criteria are met:
 
    1. PNH as documented by flow cytometry, including the presence of >10% of:
        1. PNH type III red cells (Hillmen, 2006); AND
        2.  > 40% Glycosylphosphatidylinositol-anchored proteins (GPI-AP)-deficient polymorphonuclear cells (PMNs); AND
 
2. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab (unless the clinical record documents that the risks of delaying eculizumab outweigh the risk of meningococcal infection) (FDA, 2020); AND
3. Either of the following criteria (a) OR (b) are met:
        1. The individual has: Hemoglobin that is less than or equal to 7 g/dl, or the individual has symptoms of anemia, and the hemoglobin is less than or equal to 9 g/dl (Hillmen, 2006); OR
        2. Documented history of a major adverse vascular event (MAVE) from thromboembolism (Parker, 2016)
 
4. Participation in the SOLIRIS REMS program (FDA, 2020)
 
Dosing per FDA Guidelines
 
For >18 years of age:
    • 600 mg every 7 days for the first 4weeks, followed by
    • 900 mg for the 5th dose 7 days later, then every 14 days thereafter.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
CONTINUED APPROVAL for 1 year:
Continuation of eculizumab following an initial 6-month trial for the treatment of PNH meets member benefit certificate primary coverage criteria when there is documentation of clinical improvement after the initial trial (for example, increased Hgb and Hct count or laboratory evidence of reduced hemolysis).
 
2. Atypical Hemolytic Uremic Syndrome (aHUS)
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
Eculizumab meets primary coverage criteria for the treatment of atypical hemolytic uremic syndrome (aHUS) when the following criteria are met:
 
    1. The diagnosis of aHUS is supported by the absence of Shiga toxin-producing E. coli infection (FDA, 2020); AND
    2. Thrombotic thrombocytopenic purpura (TTP) has been ruled out (for example, normal ADAMTS 13 activity and no evidence of an ADAMTS 13 inhibitor), or if TTP cannot be ruled out by laboratory and clinical evaluation, a trial of plasma exchange did not result in clinical improvement (George, 2014; Scully, 2017) AND
    3. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab (unless the clinical record documents that the risks of delaying eculizumab outweigh the risk of meningococcal infection) (FDA, 2020)
    4. Participation in the SOLIRIS REMS program (FDA, 2020)
 
Dosing per FDA Guidelines
 
For >18 years of age:
    • 900 mg weekly for the first 4 weeks, followed by
    • 1200 mg for the 5th dose 1 week later, then every 2 weeks thereafter
 
For patients less than 18 years of age, administer Soliris based upon body weight, according to the following schedule:
 
Body wt range                          Loading dose                         Maintenance dose
>40kg                                    900 mg weekly x 4 doses         1200 mg at wk 5; then every 2 wks
 30kg to <40kg                      600 mg weekly x 2 doses           900 mg at wk 3; then every 2 wks
 20kg to <30kg                      600mg weekly x 2 doses            600 mg at wk 3; then every 2 wks   
 10kg to <20kg                      600mg weekly x 1 dose              300 mg at wk 2; then every 2 wks   
  5kg to <10 kg                      300mg weekly x 1 dose              300 mg at wk 2; then every 3 wks
 
CONTINUED APPROVAL for 1 year:
Continuation of eculizumab following an initial 6- week month trial for the treatment of aHUS meets member benefit certificate primary coverage criteria when there is documentation of clinical improvement after the initial trial (for example, increased platelet count or laboratory evidence of reduced hemolysis).
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
3. Myasthenia Gravis (gMG) – (effective June 2019)
 
The use of eculizumab in the treatment of refractory chronic generalized myasthenia gravis (gMG) meets primary coverage criteria when ALL of the following criteria are met:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
    1. Individual is >18 years of age (FDA, 2020), AND
    2. A diagnosis of refractory chronic generalized Myasthenia Gravis is confirmed by a neurologist with specialization in the treatment of myasthenia gravis with Class II-IV disease (per MGFA criteria), AND member has a myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score of 6 or greater at initiation (FDA, 2020), AND
    3. There is confirmation of a positive AChR-ab (anti-acetylcholine receptor antibodies) (Howard, 2017) test and a negative MuSK (muscle-specific tyrosine kinase) antibody test. (If member is MuSK positive, then Eculizumab is only available if the member has failed or intolerant of rituximab and meets ALL of the other criteria) (Sanders, 2016) AND
    4. The individual is on stable dose of MG therapy prior to screening, that included acetylcholinesterase (AChE) inhibitors, steroids, or non-steroidal immunosuppressive therapies (NSISTs), either in combination or alone (Howard, 2021) AND
    5. The individual has received meningococcal vaccine 2 weeks prior to the initiation of eculizumab (FDA, 2020), AND
    6. The individual has documentation of inadequate response to treatment, with at least two disease modifying agents (e.g.  glucocorticoids, azathioprine, cyclosporine, methotrexate, mycophenolate, tacrolimus) over at least 12 months (Howard, 2017; Liu, 2010); AND/OR
    7. The individual has had an inadequate response to chronic intravenous immunoglobulin (IVIG) or plasmapheresis/plasma exchange over 12 months.  (Howard, 2017; Liu, 2010) AND
    8. Individual will not be receiving IVIG in combination with this product.  (FDA, 2020) AND
    9. Participation in the SOLIRIS REMS program (FDA, 2020)
 
CONTINUED APPROVAL for 1 year:
Continuation of therapy for generalized myasthenia gravis meets primary coverage criteria when:
 
    1. All the above requirements have previously been met
    2. The individual has evidence of benefit of the following:
        1. clinically significant improvement in the signs and symptoms of myasthenia gravis as documented in the medical record by a neurologist with specialization in the treatment of myasthenia gravis.
        2. improvement in the pretreatment baseline MG-ADL score and/or maintenance of score over time.
        3. IVIG is not being used concomitantly with eculizumab
 
Dosing per FDA labeling
 
    • 900 mg weekly for the first 4 weeks, followed by
    • 1200 mg for the 5th dose 1 week later, then every 2 weeks thereafter.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
4. Neuromyelitis optica spectrum disorder (NMOSD) – effective June 27, 2019
 
Eculizumab meets primary coverage criteria for the treatment of an individual with neuromyelitis optica spectrum disorder when ALL of the following are met:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
    1. The individual is > 18 yrs of age (FDA, 2020) AND
    2. A diagnosis of Neuromyelitis Optica or NMOSD (Pittock, 2019) as identified by documentation of at least one core clinical characteristic as follows:
        1. Optic neuritis
        2. Acute myelitis
        3. Area postrema syndrome – episode of otherwise unexplained hiccups or nausea and vomiting
        4. Acute brainstem syndrome
        5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions
        6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions AND
 
3.  Evidence of AQP4-IgG – Seropositive status (preferably cell-based assay) (Pittock, 2019) AND
4. A history of at least 2 relapses during the previous 12 months or 3 relapses during the previous 24 months, at least one of which had occurred within the previous 12 months (Pittock, 2019) AND
5. The use of concurrent corticosteroids limited to 20 mg per day (Pittock, 2019) AND
6. Will be ordered by or in consultation with a neurologist AND
7. Participation in the SOLIRIS REMS program (FDA, 2020) AND
8. Will not have been treated with rituximab or mitoxantrone within 3 months or IVIg within 3 weeks prior to screening (Pittock, 2019) AND
9. Will not be given concomitantly with other biologics or IVIG (FDA, 2020) AND
10. Evidence of failure of, contraindications to, or intolerance of rituximab treatment (Mealy, 2014) AND
11. Evidence of failure of, contraindication to, or intolerance of ineilizumab (Uplizna) or satralizumab (Ensprying).
 
CONTINUED APPROVAL for 1 year:
Continuation of therapy for neuromyelitis optica spectrum disorder meets primary coverage criteria when:
    1. All of the above requirements have been met.
    2. There is no evidence of relapse of the NMOSD.
 
Dosing per FDA labeling
 
    • 900 mg weekly for the first 4 weeks, followed by
    • 1200 mg for the 5th dose 1 week later, then every 2 weeks thereafter.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Eculizumab does not meet primary coverage criteria and is not covered for any other indication including but not limited to the following:
 
    1. antibody-mediated rejection in organ transplantation
    2. antineutrophil cytoplasmic autoantibody (ANCA) vasculitis
    3. antiphospholipid antibody syndrome (APS)
    4. dense deposit disease or C3 nephropathy
    5. hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia
    6.  hemolytic cold agglutinin disease
    7.  nonexudative (dry) age-related macular degeneration
    8. Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS)
    9. systemic lupus erythematosus (SLE)
    10. thrombotic thrombocytopenic purpura (TTP)
    11. concomitant use with IVIG
 
For members with contracts without primary coverage criteria, eculizumab for any other indication including, but not limited to, the indications listed above as not covered, is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
RAVULIZUMAB-cwvz (e.g., Ultomiris™)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
1. Paroxysmal Nocturnal Hemoglobinuria (PNH)
 
Ravulizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness with paroxysmal nocturnal hemoglobinuria (PNH) when ALL of the following is met:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
    1. PNH as documented by flow cytometry, including the presence of >10% of:
        1. PNH type III red cells, AND
        2. >40% glycosylphosphatidylinositol-anchored proteins (GPI-AP)-deficient polymorphonuclear cells (PMNs) (Parker, 2016) AND
2. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab OR provide 2 weeks of antibacterial drug prophylaxis if Ravulizumab must be initiated immediately and vaccines are administered less than 2 weeks before starting therapy (FDA, 2021); AND
3. Either of the following criteria are met (Parker, 2016):
        1. The individual has: Hemoglobin that is less than or equal to 7 g/dl, or the individual has symptoms of anemia, and the hemoglobin is less than or equal to 9 g/dl; OR
        2. Documented history of a major adverse vascular event (MAVE) from thromboembolism
4. Participation in the ULTOMIRIS REMS program (FDA, 2021)
 
CONTINUED APPROVAL for 1 year:
 
    1. Has met all of the initial criteria.
    2.  Documentation demonstrating a positive clinical response from baseline:
        1. Increased of stabilization of hemoglobin levels
        2. Reduction in transfusions
    3. Improvement in fatigue and quality of life.
 
Dosing and Administration per FDA Guidelines
 
The recommended dosing regimen for adult patients > 18 years with PNH consists of a loading dose followed by maintenance dosing administered by intravenous infusion.
 
    1. Starting 2 weeks after the loading dose, begin maintenance doses once every 8 weeks.  
    2. The schedule is allowed to occasionally vary within 7 days of the scheduled infusion day, (except for the first maintenance dose), but the subsequent dose should be administered according to the original schedule.   
    3. Switching from Eculizumab to Ravulizumab:
    4. 2 weeks after the last dose of Eculizumab, give the loading dose of Ravulizumab.
    5. 2 weeks after the loading dose of Ravulizumab, give maintenance dose, then once every 8 weeks after.
 
                  Body wt range                          Loading dose                      Maintenance dose
                  >40kg - <60kg                             2,400 mg                               3,000 mg
                  >60kg - >100kg                           2,700 mg                               3,300 mg
                 >100kg                                        3,000 mg                               3,600 mg
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
2. Atypical Hemolytic Syndrome (aHUS) – Effective April 6, 2020
 
Ravulizumab meets primary coverage criteria for the treatment of atypical hemolytic uremic syndrome (aHUS) when ALL of the following criteria are met:
 
INITIAL APPROVAL STANDARD REVIEW for 6 weeks:
 
    1. The diagnosis of aHUS is supported by the absence of Shiga toxin-producing E. coli infection (FDA, 2021); AND
    2. Thrombotic thrombocytopenic purpura (TTP) has been ruled out (for example, normal ADAMTS 13 activity and no evidence of an ADAMTS 13 inhibitor), or if TTP cannot be ruled out by laboratory and clinical evaluation, a trial of plasma exchange did not result in clinical improvement (George, NEJM 2014; Scully, 2017) AND
    3. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab OR provide 2 weeks of antibacterial drug prophylaxis if Ravulizumab must be initiated immediately and vaccines are administered less than 2 weeks before starting therapy (FDA, 2021); AND
    4. Participation in the ULTOMIRIS REMS program (FDA, 2021)
 
CONTINUED APPROVAL for 1 year:
Continuation of ravulizumab following an initial 6-week trial for the treatment of aHUS meets member benefit certificate primary coverage criteria when there is documentation of clinical improvement after the initial trial (for example, increased platelet count or laboratory evidence of reduced hemolysis).
 
Dosing and Administration
 
For adults and pediatric patients with aHUS, administer Ravulizumab based upon body weight, according to the following schedule:
 
         Body wt range              Loading dose                     Maintenance dose
        >5kg to <10 kg              600 mg x 1 dose                300 mg every 4 wks
        >10kg to <20kg             600 mg x 1 dose                600 mg every 4 wks
         >20kg to <30kg              900 mg x1 dose                 2,100 mg every 8 wks   
         >30kg to <40kg             1,200 mg x 1 dose              2,700 mg every 8 wks  
         >40kg to <60 kg            2,400 mg x 1 dose              3,000 mg every 8 wks  
        >60kg to <100kg           2,700 mg x 1 dose              3,300 mg every 8 wks
          >100kg                         3,000 mg x 1 dose               3,600 mg every 8 wks
 
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
2. Generalized Myasthenia Gravis (gMG) – Effective April 27, 2022
 
Ravulizumab meets primary coverage criteria for the treatment of generalized myasthenia gravis (gMG) when ALL of the following criteria are met:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
    1. Diagnosed with MG at least 6 months (180 days) prior to the date of screening visit. (FDA, 2022)
    2. MG Foundation of America Clinical Classification Class II to IV at screening (FDA, 2022)
    3. MG-ADL profile must be greater than or equal to 6 at screening and randomization (Day 1) (FDA, 2022).
    4. Evidence of a positive serologic test for anti-acetylcholine receptor (AChR) antibodies (FDA, 2022); AND
    5. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab OR provide 2 weeks of antibacterial drug prophylaxis if Ravulizumab must be initiated immediately and vaccines are administered less than 2 weeks before starting therapy (FDA, 2021); AND
    6. The individual has documentation of inadequate response to treatment, with at least two disease modifying agents (e.g.  glucocorticoids, azathioprine, cyclosporine, methotrexate, mycophenolate, tacrolimus) over at least 12 months (Howard, 2017; Liu, 2010); AND/OR
    7. The individual has had an inadequate response to chronic intravenous immunoglobulin (IVIG) or plasmapheresis/plasma exchange over 12 months.  (Howard, 2017; Liu, 2010) AND
    8. Individual will not be receiving IVIG in combination with this product.  (FDA, 2020) AND
    9. Participation in the ULTOMIRIS REMS program (FDA, 2022)
 
CONTINUED APPROVAL for 1 year:
Continuation of ravulizumab following initial approval for the treatment of gMG meets member benefit certificate primary coverage criteria when there is documentation of clinical improvement.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Ravulizumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other condition than including but not limited to:
    1. antibody-mediated rejection in organ transplantation
    2. antineutrophil cytoplasmic autoantibody (ANCA) vasculitis
    3. antiphospholipid antibody syndrome (APS)
    4. dense deposit disease or C3 nephropathy
    5. hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia
    6. hemolytic cold agglutinin disease
    7. nonexudative (dry) age-related macular degeneration
    8. Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS)
    9. systemic lupus erythematosus (SLE)
    10. thrombotic thrombocytopenic purpura (TTP)
    11. concomitant use with IVIG
 
For members with contracts without primary coverage criteria, Ravulizumab is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to June 1, 2022 are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com

Rationale:
Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
 
2019 Update
Ravulizumab
A phase 3 study showed Ravulizumab (ALXN1210), a new complement C5 inhibitor, provided immediate, complete, and sustained C5 inhibition. This phase 3, open-label study (Lee, JW, Sicre de Fontbrune, F, Wong Lee Lee, L et al. 2018), assessed the non-inferiority of ravulizumab to eculizumab in complement inhibitor-naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) 1.5 times the upper limit of normal and at least one PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N=246). Co-primary efficacy endpoints were proportion of patients remaining transfusion-free and LDH normalization. Secondary endpoints were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was non-inferior to eculizumab for both co-primary and all key secondary endpoints (Pinf < .0001): transfusion avoidance (73.6% versus 66.1%; difference of 6.8% [95% confidence interval (CI), -4.66, 18.14]), LDH normalization (53.6% versus 49.4%, odds ratio [1.19 (0.80, 1.77)]), percent reduction in LDH (-76.8% versus -76.0%; difference [95% CI], -0.83% [-5.21, 3.56]), change in FACIT-Fatigue score (7.07 versus 6.40; difference [95% CI], 0.67 [-1.21, 2.55]), breakthrough hemolysis (4.0% versus 10.7%; difference [95% CI], -6.7% [-14.21, 0.18]), and stabilized hemoglobin (68.0% versus 64.5%; difference [95% CI], 2.9 [-8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved non-inferiority compared with eculizumab given every 2 weeks for all efficacy endpoints, with a similar safety profile. This trial was registered at https://ClinicalTrials.gov #NCT02946463.
 
 
A second study has shown that Ravulizumab administered every 8 weeks, was non-inferior to eculizumab administered every 2 weeks in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study (Kulasekararaj AG, Hill A,Rottinghause, ST, et al. 2018), assessed non-inferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for greater than 6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy endpoint was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary endpoints included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was non-inferior to eculizumab (Pinf<.0006 for all endpoints), including percentage change in LDH (difference, 9.21% [95% CI: -0.42 to 18.84], P = 0.058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI: -8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI: -0.21 to 3.15]), transfusion avoidance (difference of 5.5 [95% CI: -4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI: -10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. (Funded by Alexion Pharmaceuticals, Inc., ClinicalTrials.gov: NCT03056040).
 
 2019 Update
 Eculizumab for Myasthenia Gravis
(Howard JF Jr, Utsugisawa K. Benatar M, et al) performed a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. Participants were randomly assigned (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo.
 
Between April 30, 2014, and Feb 19, 2016, 125 patients were randomly assigned and treated, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy.
 
The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. This trial is registered with ClinicalTrials.gov, number NCT01997229.
 
June 2019 Update
In an interim analysis of the REGAIN study, 117 of the 118 patients who completed REGAIN enrolled in the open-label study (eculizumab/eculizumab, 56; placebo/eculizumab, 61) and were included in the safety analysis, and 116 patients were included in the efficacy analysis (eculizumab/eculizumab, 56; placebo/eculizumab, 60); approval for the inclusion of 1 patient in the interim efficacy analyses was not given by their national health authority. The myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001).  Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001).
 
Results of this interim analysis confirm the rapid and robust response to eculizumab that was observed during REGAIN and support the long-term clinical effectiveness and safety of eculizumab in patients with AChR+ refractory gMG who previously experienced persistent symptoms and significant morbidities despite concomitant IST. Improvements in activities of daily living, muscle strength, functional ability, and quality of life were maintained through 3 years in patients receiving eculizumab. This study also provides new evidence for other clinical benefits of eculizumab in these patients, including reducing the frequency of disease exacerbations. [Muppidi S, Utsugisawa K, Benatar M, et al. 2019]
 
An investigation of the effect of eculizumab versus placebo on fatigue in patients with AChR+ refractory
gMG, also assessed the relationship between fatigue and MG-specific measures. The Neuro-QOL Fatigue subscale was used to evaluate changes in patients’ self-reported assessment of fatigue during REGAIN and its open-label extension study.  We also measured the correlation between outcomes measured using the Neuro-QOL Fatigue subscale and the MG-ADL, QMG, and MG-QOL15 scales in REGAIN.
 
REGAIN was a 26-week, phase 3, randomized, double blind, placebo-controlled study evaluating eculizumab efficacy and safety. Patients were randomized 1:1 to receive eculizumab (n = 62; induction: 900 mg for 4 weeks; maintenance: 1200 mg at week 4 and then every2 weeks until week 26) or placebo (n = 63). The primary endpoint was the change in MG-ADL total score with eculizumab versus placebo.
 
The Neuro-QOL Fatigue subscale was used to assess fatigue, and the MG-ADL, QMG, and MG-QOL15 scales were used to measure MG-specific activities of daily living, muscle strength, and quality of life, respectively.
 
At REGAIN week 26, eculizumab-treated patients showed significantly greater improvements in Neuro-QOL Fatigue scores than placebo-treated patients (consistent with improvements in MG-ADL, QMG, and MG-QOL15 scores previously reported in REGAIN). Improvements with eculizumab were sustained through OLE week 52. Correlations between Neuro-QOL Fatigue and MG-QOL15, MG-ADL, and QMG scores were strong for eculizumab-treated patients at REGAIN week 26, and strong, moderate, and weak, respectively, for placebo-treated patients.  [Anderson H, Mantegazza R, Wang JJ, et al. 2019]
 
Update July 2019
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune, inflammatory disorder of the central nervous system that has a prevalence of 0.5to 10 persons (predominantly women) per 100,000 population.  It is characterized by recurrent optic neuritis and myelitis, and are frequently associated with poor recovery.  Immunosuppressive therapies, including rituximab, are used for relapse prevention in NMOSD without regulatory approval, but 25 to 60% of patients receiving these medications continue to have recurrent attacks. [Pittock S.J. Berthele A, Fujihara, H.J., et al 2019]
 
Aquaporin-4 (AQP4) is a water channel protein expressed mainly by astrocytes in the central nervous
system. Antibodies of the IgG class against AQP4 are present in 65 to 88% of patients with NMOSD. Data indicates that AQP4-IgG triggers the complement cascade, which leads to inflammation and the formation of the membrane attack complex. The membrane attack complex is implicated in astrocyte destruction and neuronal injury but is not seen in experimental models in the presence of a complement inhibitor. [Pittock S.J. Berthele A, Fujihara, H.J., et al 2019]
 
The efficacy and safety of eculizumab in patients with AQP4-IgG-positive NMOSD was evaluated in a phase 3, randomized, double-blind, placebo–controlled, time –to-event trial (Prevent).  96 patients received eculizumab and 47 placebo.  91% of the patients were women.  Of the 143 patients, 32% had received rituximab previously but not within 3 months before screening.  24% did not receive any concomitant immunosuppressive therapy during the trial.  83% of those receiving eculizumab completed the trial, while 94% on placebo completed the trial.  In the eculizumab group, 12 withdrew, 3 were lost to follow-up and 1 died (from pulmonary empyema).  The primary end point of adjudicated relapse occurred in 3% of the eculizumab group and 43% of the placebo group (hazard ratio, 0.06; 95% confidence interval [CI}, 0.02 to 0.20; P<0.001).  The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ration, 0.04; 95% CI, 0.01 to 0.15; P<0.001).  Among the patients with aQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. [Pittock S.J. Berthele A, Fujihara, H.J., et al 2019]
 
2020 Update
A phase 3, randomized, placebo-controlled REGAIN study was conducted to evaluated the effect of eculizumab on perceived fatigue in patients with anti-acetylcholine receptor antibody-positive, refractory, generalized myasthenia gravis using the Quality of Life in Neurological Disorder Fatigue subscale, and to evaluate correlations between improvements in Neuro-QOL Fatigue and other clinical endpoints.
At REGAIN week 26, eculizumab-treated patients showed significantly greater improvements in Neuro-QOL Fatigue scores than placebo-treated patients (consistent with improvements in MG-ADL, QMG, and MG-QOL15 scores previously reported in REGAIN). Improvements with eculizumab were sustained through OLE week 52. Correlations between Neuro-QOL Fatigue and MG-QOL15, MG-ADL, QMG, and MG-QOL15 scores previously reported in REGAIN). Improvements with eculizumab were sustained through OLE week 52. Correlations between Neuro-QOL Fatigue and MG-QOL15, MG-ADL, and QMG scores were strong for eculizumab-treated patients at REGAIN week 26, and strong, moderated, and weak, respectively, for placebo-treated patients.
Compared with placebo, eculizumab was associated with improvements in perceived fatigue that strongly correlated with improvements in MG-specific outcome measures. (Andersen H, Mantegazza R, Wang JJ, et al., 2019)
 
 2020 Update
Ravulizumab for atypical hemolytic uremic syndrome (aHUS)
A global phase 3, single arm study in complement inhibitor-naïve adults (18 years and older) was performed with a total of 56 adult patients with aHUS (Rondeau E et al. 2020). Ninety-three percent of patients had extrarenal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 71.4% (n = 40) of patients had Stage 5 chronic kidney disease (CKD). Fourteen percent had a medical history of kidney transplant and 51.8% were on dialysis at study entry. Eight patients entered the study with evidence of TMA for > 3 days after childbirth (ie, postpartum). One additional patient had a Complete TMA Response that was confirmed after the 26-week Initial Evaluation Period. Complete TMA Response was achieved at a median time of 86 days (range: 7 to 169 days). The median duration of Complete TMA Response was 7.97 months (range: 2.52 to 16.69 months). All responses were maintained through all available follow-up. Other endpoints included platelet count change from baseline, dialysis requirement, and renal function as evaluated by estimated glomerular filtration rate (eGFR). An increase in mean platelet count was observed after commencement of Ultomiris at Day 8 and remaining above 227 × 109 /L at all subsequent visits in the Initial Evaluation Period (26 weeks). Renal function, as measured by eGFR, was improved or maintained during therapy. The mean eGFR increased from 15.86 (14.82) at baseline to 51.83 (39.16) by 26 weeks. In patients with Complete TMA Response, renal function continued to improve after the Complete TMA Response was achieved. Seventeen of the 29 patients (59%) who required dialysis at study entry discontinued dialysis by the end of the available follow-up and 6 of 27 (22%) patients were off dialysis at baseline were on dialysis at last available follow-up (Alexion Pharma 2019b).
 
September 2020 Update
Relapse rates were annualized in a retrospective, multicenter analysis of relapses in 90 patients with NMO and NMO spectrum disorder treated with azathioprine, mycophenolate, and/or rituximab at the Mayo Clinic and the Johns Hopkins Hospital during the past 10 year.   
Rituximab reduced the relapse rate up to 88.2%, with 2 in 3 patients achieving complete remission. Mycophenolate reduced the relapse rate by up to 87.4%, with a 36% failure rate. Azathioprine reduced the relapse rate by 72.1% but had a 53% failure rate despite concurrent use of prednisone.
Initial treatment with rituximab, mycophenolate, and, to a lesser degree, azathioprine significantly reduces relapse rates in NMO and NMO spectrum disorder patients. Patients for whom initial treatment fails often achieve remission when treatment is switched from one to another of these drugs. (Mealy MA, Wingerchuk DM, Palace J, Greenberg BM, Levy M., 2014)
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2021. No new literature was identified that would prompt a change in the coverage statement.
 
September 2021 Update
Eculizumab, a recombinant humanized monoclonal IgG2/4 antibody selectively inhibits the terminal portion of the complement system by specifically binding to the terminal C5, which acts at a late stage in the complement cascade.  Inhibition of the complement cascade at this point, preserves the normal, disease-preventing functions of proximal complement system while impeding the properties of C5 that promote inflammation and cell destruction. As a recombinant humanized monoclonal antibody that binds to complement protein C5, eculizmab effectlively inhibits enzymatic cleavage and blocks formation of the terminal complement complex, preventing red cell lysis in paroxysmal nocturnal hemoglobinuria (PNH) and complement-mediated thrombotic microangiopathy in atypical hemolytic uremic syndrome (aHUS).
 
On March 16, 2007, Eculizumab (Soliris®; Alexion Pharmaceuticals, Inc. Cheshire, CT), a humanized monoclonal antibody that binds to the human C5 complement protein, received accelerated approval by the U.S. Food and Drug Administration for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis.  Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem disorder clinically characterized by chronic complement-mediated hemolysis, thrombosis, and bone marrow failure. Thrombosis, the major cause of death in PNH, is observed in approximately 40% of patients. The symptoms associated with this disorder, including fatigue, pain, esophageal spasm, and erectile dysfunction, are often severe and disabling.
 
On Sep 23, 2011 the U.S. Food and Drug Administration (FDA) approved Eculizumab (Soliris®) for the treatment of all pediatric and adult patients with atypical hemolytic uremic syndrome (aHUS).  Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. Typical (acquired) HUS is triggered by infectious agents such as strains of E. coli (Stx-E. coli) that produce powerful Shiga-like exotoxins, whereas atypical HUS (aHUS) can be genetic, acquired, or idiopathic (of unknown cause). Onset of atypical HUS ranges from prenatal to adulthood. Individuals with genetic atypical HUS frequently experience relapse even after complete recovery following the presenting episode. Sixty percent of genetic aHUS progresses to end-stage renal disease (ESRD).
 
In 10/2017, the FDA approved Eculizumab for the treatment of adult patients with generalized Myasthenia Gravis (gMg) who are anti-acetylcholine receptor (AChR) antibody positive.  MG is a common disorder of neuromuscular transmission characterized by a variable combination of weakness in ocular, bulbar, limb, and respiratory muscles.  Autoantibodies to the acetylcholine receptor is present in 73% - 88% of patients with gMG. In the REGAIN study (NCT01997229), Eculizumab produced meaningful improvements in ADL’s, muscle strength, functional ability and quality of life in those patients with AchR refractory gMG.
 
Eculizumab was also approved for neuromyelitis optic spectrum disorder (NMOSD) in adult patients who are anti-aquapoin-4 (AQP4-IgG) antibody positive on June 27, 2019.  NMOSD is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of the cases are associated with AQP4-IgG and complement-mediated damage to the central nervous system.
 
Ravulizumab-cwvz (Ultomiris™)
Ravulizumab is a humanized monoclonal antibody to complement component C5, engineered from Soliris.  It specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal compliment complex [C5b-9]) and preventing the generation of the terminal complement C5b9.  Ravulizumab inhibits terminal complement-mediated intravascular hemolysis in patient with paroxysmal nocturnal hemoglobinuria (PNH).
 
Complement inhibitors have black box warnings for serious meningococcal infections. Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors and meningococcal infection may become rapidly life-threating or fatal if not recognized and treated early. Individuals should be immunized with meningococcal vaccines at least 2 weeks prior to initiation of therapy unless the risks of delaying therapy outweigh the risk of developing a meningococcal infection. The FDA has required the manufacturers to develop comprehensive risk management programs that include the enrollment of prescribers in the Soliris REMS or Ultomiris REMS Programs respectively. Additional information and forms for individuals, prescribers, and pharmacists may be found on the manufacturer’s websites: http://www.solirisrems.com or http://www.ultomirisrems.com.
 
May 2022 Update
The efficacy of ULTOMIRIS for the treatment of gMG was demonstrated in a randomized, double-blind, placebo-controlled, multicenter study (ALXN1210-MG-306; NCT03920293). Patients were randomized 1:1 to either receive ULTOMIRIS (n=86) or placebo (n=89) for 26 weeks. ULTOMIRIS was administered intravenously according to the weight-based recommended dosage.
 
Patients with gMG with a positive serologic test for anti-AChR antibodies, Myasthenia Gravis Foundation of America (MGFA) clinical classification class II to IV, and Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score 6 were enrolled.
 
Baseline and disease characteristics were similar between treatment groups (including age at first dose [mean of 58 years for ULTOMIRIS versus 53 years for placebo], gender [51% female for ULTOMIRIS versus 51% female for placebo], race as White, Asian, and Black or African American [78%, 17%, and 2% for ULTOMIRIS versus 69%, 18%, and 5% for placebo, respectively], and duration of MG since diagnosis [mean of 10 years, ranging from 0.5 to 39.5 years, for ULTOMIRIS versus mean of 10.0 years, ranging from 0.5 to 36.1 years, for placebo].
 
Over 80% of patients were receiving acetylcholinesterase inhibitors, 70% were receiving corticosteroids, and 68% were receiving non-steroidal immunosuppressants (ISTs) at study entry. Patients on concomitant medications to treat gMG were permitted to continue on therapy throughout the course of the study.
 
The primary efficacy endpoint was a comparison of the change from baseline between treatment groups in the MG-ADL total score at Week 26. The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function. The total score ranges from 0 to 24, with the higher scores indicating more impairment.
 
The secondary endpoints, also assessed from baseline to Week 26, included the change in the Quantitative MG total score (QMG). The QMG is a 13-item categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness. A total score ranges from 0 to 39, where higher scores indicate more severe impairment.
 
Other secondary endpoints included the proportion of patients with improvements of at least 5 and 3 points in the QMG and MG-ADL total scores, respectively.
 
Treatment with ULTOMIRIS demonstrated a statistically significant change in the MG-ADL and QMG total scores from baseline at Week 26 as compared to placebo.
 
The proportion of QMG responders with at least a 5-point improvement at week 26 was greater for ULTOMIRIS (30.0%) compared to placebo (11.3%) p = 0.005. The proportion of MG-ADL responders with at least a 3-point improvement at week 26 was also greater for ULTOMIRIS (56.7%) compared to placebo (34.1%). The proportion of clinical responders at higher response thresholds (4-, 5-, 6-, 7-, or 8-point improvement on MG-ADL, and 6-, 7-, 8-, 9-, or 10-point improvement on QMG) was consistently greater for ULTOMIRIS compared to placebo. (FDA 2022)
October 2022 Update
The Institute for Clinical and Economic Review (ICER) published a review for eculizumab and efgartigimod for the treatment of myasthenia gravis.  It identified one Phase III trial each for eculizumab (REGAIN) and efgartigimod (ADAPT) but found insufficient data to compare these drugs to maintenance intravenous immunoglobulin IVIG and rituximab (RTX).  In the Phase III REGAIN trial, patients with anti-AChR antibody positive, treatment-resistant gMG who received eculizumab had significantly better improvement in the myasthenia gravis activities of daily living (MG-ADL) and quantitative myasthenia gravis (QMG) scores than those on placebo at four weeks and eight weeks, and the improvements were sustained at 26 weeks.  In addition, at week 26, the proportion of patients with minimal symptom expression (MG-ADL score of 0 or 1) was much greater in the eculizumab group (21.4% vs. 1.7%, p=0.0007) [Vissing J et al., 2020]  In the open label extension through 130 weeks of follow up, the benefits were maintained, and may have increased compared with 26 weeks [Mantegazza R, et al., 2021]  There were no excess adverse events (AEs) in the trials, although more patients in the eculizumab group stopped treatment due to AEs, and it carries a black box warning for meningococcal infections.  
 
The Phase III ADAPT trial was conducted in gMG patients with or without anti-AChR-antibody; however, the primary outcome was in the subgroup of anti-AChR antibody positive patients.  The proportion of patients with clinically meaningful improvement (2-point MG-ADL improvement sustained for 4 weeks) was much greater in the efgartigimod group compared to the placebo group.  Anti-AChR antibody positive gMG patients who received efgartigimod did significantly better on MG-ADL and QMG than those who received placebo.  However, the improvements were greater at four weeks than at eight weeks, reflecting the unusual dosing schedule in the trial.
 
Patients received their second treatment cycle only when they no longer had a clinically meaningful improvement on the MG-ADL.  Thus, many patients were back near baseline at eight weeks.  The anti-AChR antibody negative patients randomized to efgartigimod were only slightly more likely to respond based on the MG-ADL (68% vs. 63% in placebo group, p=NR).  AEs did not appear to be more common with efgartigimod, but there are long-term concerns about infections with lowering of IgG levels.
 
One important area of uncertainty is that it is not clear if or when to stop either of the drugs in patients who are responding to them.  For efgartigimod, the primary uncertainty is the appropriate dosing regimen.  In the ADAPT trial, subsequent cycles were started once patients lost clinical benefits.  It seems likely that in routine practice, patients and clinicians will not want to wait until the benefits have receded before starting another round of therapy.  Also, despite their use in clinical practice, there is a lack of comparative efficacy data for both rituximab and IVIG used as maintenance therapy for gMG.  
 
Taking into consideration the above information on the benefits and AEs of eculizumab, it was concluded that there is moderate certainty of a small or substantial net health benefit with high certainty of at least a small benefit for eculizumab added to conventional therapy (B+) in adults with gMG positive for anti-AChR antibodies “refractory” to conventional therapy.  For efgartigimod, given the above information on short-term benefits, but uncertainties about dosing, long-term benefits, and long-term safety, it was concluded that that there is moderate certainty of a comparable, small, or substantial net health benefit of efgartigimod added to conventional therapy with high certainty of at least comparable net health benefit (C++) in adults with gMG positive for anti-AChR antibodies.  While there is evidence for efgartigimod in adults with gMG negative for anti-AChR antibodies, it is sparse and of uncertain clinical and statistical significance.  Thus, it was concluded that the evidence was insufficient (I) to distinguish the net health benefit of efgartigimod added to conventional therapy from conventional therapy alone in patients who test negative for anti-AChR antibodies.  In addition, the evidence is insufficient (I) to distinguish the net health benefits of rituximab and IVIG from placebo, eculizumab, and efgartigimod.
 

CPT/HCPCS:
C9052Injection, ravulizumab cwvz, 10 mg
C9399Unclassified drugs or biologicals
J1300Injection, eculizumab, 10 mg
J1303Injection, ravulizumab cwvz, 10 mg
J3590Unclassified biologics

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