| Coverage Policy Manual | |
| Policy #: | 2016013 |
| Category: | Pharmacy |
| Initiated: | May 2016 |
| Last Review: | October 2022 |
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| Ravulizumab-cwvz (e.g., Ultomiris) | |
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| Description: |
Ravulizumab-cwvz 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-cwvz inhibits terminal complement-mediated intravascular hemolysis in individual with paroxysmal nocturnal hemoglobinuria (PNH).
Regulatory Status
On December 21, 2018, the FDA granted both priority review and Orphan Drug designation for Ravulizumab-cwvz for the indication of PNH.
On October 18, 2019, Ravulizumab-cwvz was FDA approval for treating adults and pediatric individuals one month or older for atypical hemolytic uremic syndrome (aHus).
On April 27, 2022, the Food and Drug Administration approved ravulizumab-cwvz (e.g., Ultomiris) for the treatment of adult individuals with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive.
Complement inhibitors such as ravulizumab-cwvz have black box warnings for serious meningococcal infections. Life-threatening and fatal meningococcal infections have occurred in individuals 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 manufacturers to develop comprehensive risk management programs that include the enrollment of prescribers and dispensing pharmacies in Ultomiris Risk Evaluation and Mitigation Strategies (REMS) Program.
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
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 law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart 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 Date April 3, 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ravulizumab-cwvz-cwvz intravenous solution meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
Generalized Myasthenia Gravis (gMG)
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
Paroxysmal Nocturnal Hemoglobinuria (PNH)
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
Atypical Hemolytic Syndrome (aHUS)
INITIAL APPROVAL STANDARD REVIEW for 6 weeks:
CONTINUED APPROVAL for no more than 1 year:
REINITIATION of ravulizumab-cwvz for aHUS:
Requests for reinitiation of ravulizumab-cwvz in aHUS may be approved if the following criteria are met (Fakhouri 2017):
Policy Guidelines
Myasthenia Gravis Foundation of America (MGFA) Clinical Classification:
Myasthenia Gravis Activities of Daily Living Scale (MG-ADL):
The MG-ADL scale assesses the impact of gMG on daily functions of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale; a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function. A total score ranges from 0 to 24, with the higher scores indicating more impairment. Score grade items are as follows (Wolfe, 1999):
Talking
Chewing
Swallowing
Breathing
Impairment of ability to brush teeth or comb hair
Impairment of ability to arise from a chair
Double vision
Eyelid droop
Dosage and Administration
Dosing per FDA Guidelines
IV administration: The recommended dosing for adults and pediatric individuals 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 4 weeks
> 10kg - < 20 kg 600 mg 600 mg every 4 weeks
> 20 kg - < 30 kg 900 mg 2,100 mg every 8 weeks
> 30kg - < 40 kg 1,200 mg 2,700 mg every 8 weeks
> 40kg - < 60 kg 2,400 m 3,000 mg every 8 weeks
> 60kg - < 100 kg 2,700 mg 3,300 mg every 8 weeks
> 100 kg 3,000 mg 3,600 mg every 8 weeks
Myasthenia Gravis
The recommended dosing for adults and pediatric individuals with gMG consists of a loading dose followed by maintenance dosing by IV infusion beginning 2 weeks following the loading dose.
Body weight range Loading dose Maintenance dose
> 40kg to <60 kg 2,400 mg x 1 dose 3,000 mg every 8 weeks
> 60kg to <100kg 2,700 mg x 1 dose 3,300 mg every 8 weeks
> 100kg 3,000 mg x 1 dose 3,600 mg every 8 weeks
Ravulizumab-cwvz IV solution for injection is available in 3 vial strengths and sizes:
Ravulizumab-cwvz IV solution for injection should be administered by a healthcare professional.
Please refer to 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-cwvz, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, ravulizumab-cwvz, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective October 2023 to April 2, 2024
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:
Paroxysmal Nocturnal Hemoglobinuria (PNH)
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for 1 year:
Atypical Hemolytic Syndrome (aHUS)
INITIAL APPROVAL STANDARD REVIEW for 6 weeks:
CONTINUED APPROVAL for no more than 1 year:
REINITIATION of ravulizumab for aHUS:
Requests for reinitiation of ravulizumab in aHUS may be approved if the following criteria are met (Fakhouri 2017):
Generalized Myasthenia Gravis (gMG)
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for 1 year:
Continuation of ravulizumab following initial approval for the treatment of gMG meets primary coverage criteria when:
Dosing and Administration
Dosing per FDA Guidelines
Note: Refer to package insert for details surrounding transitions from eculizumab, scheduling and most recent dosing recommendations.
Paroxysmal Nocturnal Hemoglobinuria (PNH) and Atypical Hemolytic Syndrome (aHUS)
IV administration: The recommended dosing for adults and pediatric individuals 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 4 weeks
>10kg - <20 kg 600 mg 600 mg every 4 weeks
>20 kg - <30 kg 900 mg 2,100 mg every 8 weeks
>30kg - <40 kg 1,200 mg 2,700 mg every 8 weeks
>40kg - <60 kg 2,400 m 3,000 mg every 8 weeks
>60kg - <100 kg 2,700 mg 3,300 mg every 8 weeks
>100 kg 3,000 mg 3,600 mg every 8 weeks
Myasthenia Gravis
The recommended dosing for adults and pediatric individuals with gMG consists of a loading dose followed by maintenance dosing by IV infusion beginning 2 weeks following the loading dose.
Body weight range Loading dose Maintenance dose
>40kg to <60 kg 2,400 mg x 1 dose 3,000 mg every 8 weeks
>60kg to <100kg 2,700 mg x 1 dose 3,300 mg every 8 weeks
>100kg 3,000 mg x 1 dose 3,600 mg every 8 weeks
Ravulizumab IV solution for injection is available in 3 vial strengths and sizes:
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.
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.
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to October 2023, are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
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| 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, assessed the non-inferiority of ravulizumab to eculizumab in complement inhibitor-naive adults with paroxysmal nocturnal hemoglobinuria (PNH) (Lee, 2018). 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 assessed non-inferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy (Kulasekararaj, 2018). 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
A phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) was performed in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia (Howard, 2017). 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, 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, 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, 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, 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, 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, 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, 2019).
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, 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, 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, 2021). There were no excess adverse events (AEs) in the trials, although more patients in the eculizumab group stopped treatment due to AEs, and it carries a black box warning for meningococcal infections.
The Phase III ADAPT trial was conducted in gMG patients with or without anti-AChR-antibody; however, the primary outcome was in the subgroup of anti-AChR antibody positive patients. The proportion of patients with clinically meaningful improvement (≥2-point MG-ADL improvement sustained for ≥4 weeks) was much greater in the efgartigimod group compared to the placebo group. Anti-AChR antibody positive gMG patients who received efgartigimod did significantly better on MG-ADL and QMG than those who received placebo. However, the improvements were greater at four weeks than at eight weeks, reflecting the unusual dosing schedule in the trial.
Patients received their second treatment cycle only when they no longer had a clinically meaningful improvement on the MG-ADL. Thus, many patients were back near baseline at eight weeks. The anti-AChR antibody negative patients randomized to efgartigimod were only slightly more likely to respond based on the MG-ADL (68% vs. 63% in placebo group, p=NR). AEs did not appear to be more common with efgartigimod, but there are long-term concerns about infections with lowering of IgG levels.
One important area of uncertainty is that it is not clear if or when to stop either of the drugs in patients who are responding to them. For efgartigimod, the primary uncertainty is the appropriate dosing regimen. In the ADAPT trial, subsequent cycles were started once patients lost clinical benefits. It seems likely that in routine practice, patients and clinicians will not want to wait until the benefits have receded before starting another round of therapy. Also, despite their use in clinical practice, there is a lack of comparative efficacy data for both rituximab and IVIG used as maintenance therapy for gMG.
Taking into consideration the above information on the benefits and AEs of eculizumab, it was concluded that there is moderate certainty of a small or substantial net health benefit with high certainty of at least a small benefit for eculizumab added to conventional therapy (B+) in adults with gMG positive for anti-AChR antibodies “refractory” to conventional therapy. For efgartigimod, given the above information on short-term benefits, but uncertainties about dosing, long-term benefits, and long-term safety, it was concluded that that there is moderate certainty of a comparable, small, or substantial net health benefit of efgartigimod added to conventional therapy with high certainty of at least comparable net health benefit (C++) in adults with gMG positive for anti-AChR antibodies. While there is evidence for efgartigimod in adults with gMG negative for anti-AChR antibodies, it is sparse and of uncertain clinical and statistical significance. Thus, it was concluded that the evidence was insufficient (I) to distinguish the net health benefit of efgartigimod added to conventional therapy from conventional therapy alone in patients who test negative for anti-AChR antibodies. In addition, the evidence is insufficient (I) to distinguish the net health benefits of rituximab and IVIG from placebo, eculizumab, and efgartigimod.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2023. No new literature was identified that would prompt a change in the coverage statement. Split ravulizumab and eculizumab policies into two separate policies.
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Br J Haematol. 2012; 157(6):772-774. Howard JF Jr, Utsugisawa K. Benatar M, et al.(2017) Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017; Dec;16(12):976-986. doi: 10.1016/S1474-4422(17)30369-1. Epub 2017 Oct 20. Howard JF Jr, Utsugisawa K. Benatar M, et al.(2017) Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017; Dec;16(12):976-986. doi: 10.1016/S1474-4422(17)30369-1. Epub 2017 Oct 20. Jodele S, Dandoy CE, Lane A, et al.(2020) Complement blockade for TA-TMA: lessons learned from large pediatric cohort treated with eculizumab. Blood. 2020 Jan 13. pii: blood.2019004218. doi: 10.1182/blood.2019004218. [Epub ahead of print] Kulasekararaj AG, Hill A,Rottinghause, ST, et al.(2018) Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2018 Dec 3. pii: blood-2018-09-876805. doi: 10.1182/blood-2018-09-876805. [Epub ahead of print] Lee,JW, Sicre deFontbrune F, Wong Lee Lee L, et al(2018) Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naïve to complement inhibitors: the 301 study. . Blood. 2018 Dec 3. Pii:blood-2018-09-876136. doi: 10.1182/blood-2018-09-876136. [Epub ahead of print] Mantegazza R, Wolfe GI, Muppidi S, et al.(2021) Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension. Neurology. 2021;96:e610-e618. Mealy MA, Wingerchuk DM, Palace J, Greenberg BM, Levy M.(2014) Comparison of Relapse and Treatment Failure Rates Among Patients With Neuromyelitis Optica: Multicenter Study of Treatment Efficacy . 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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association. |
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