Coverage Policy Manual
Policy #: 2020016
Category: Pharmacy
Initiated: July 2020
Last Review: July 2024
  Inebilizumab-cdon (e.g., Uplizna™)
Description:
Inebilizumab-cdon is a CD19-directed cytolytic antibody for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult individuals who are anti-aquaporin-4 (AQP4) antibody positive. It is a genetically humanized monoclonal antibody that binds to CD19, a cell surface antigen that is present on pre-B and mature B cell lymphocytes.  
 
NMOSD is an autoimmune disorder, (previously known as Devic disease), of the central nervous system that predominantly affects the optic nerves and spinal cord.  Estimates of prevalence and incidence vary, but it ranges from 0.5 to 10 per 100,000.  The incidence of NMOSD is up to 10 times higher in women than men and is more prevalent in Asians and
Africans.  Signs and symptoms include myelitis, ocular pain, temporary vision loss and weakness is the arms and legs.
 
Regulatory Status
 
On January 1, 2021 J1823 will be effective for inebilizumab-cdon  (e.g., Uplizna™).  Services billed as of January 1, 2021 and after will be expected to be billed with this code.
 
Coding
 
See CPT/HCPCS Code section below.
     
Policy/
Coverage:
Effective July 1, 2020 prior approval is required for inebilizumab-cdon.
 
The use of this drug 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.
 
Effective July 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Inebilizumab-cdon meets primary coverage criteria that there be scientific evidence  of effectiveness in improving health outcomes when ALL of the following criteria are met:
 
Initial Treatment (6-month approval)
 
    1. Individual is 18 years of age or older (Cree, 2019); AND
    2. Individual has a diagnosis of Neuromyelitis Optica or NMOSD as identified by documentation of at least one core clinical characteristic as follows:
a. Optic neuritis; OR
b. Acute myelitis; OR
c. Area postrema syndrome- episode of otherwise unexplained hiccups or nausea and vomiting; OR
d. Acute brainstem syndrome; OR
e. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions; OR
f. Symptomatic cerebral syndrome with NMOSD-typical brain lesions; AND
3. Evidence of AQP4-IgG – Seropositive status (preferably cell based assay)  (Wingerchuk, 2015); AND
4. Individual has a history of at least 2 relapses during the previous 24 months or at least one which had occurred within the previous 12 months (Cree, 2019); AND
5. Individual has an Expanded Disability Status Scale (EDSS) score of 8.0 or less (Cree, 2019); AND
6. May have use of concurrent corticosteroids limited to 20 mg per day; AND
7. Will be ordered by or in consultation with a neurologist; AND
8. Will not be given concomitantly with other biologics or IVIG (Uplinza, 2020); AND
9. Evidence of failure of, contraindication to, or intolerance of rituximab treatment (Mealy, 2014); AND
10. Must be dosed in accordance with the FDA label.
 
Continued Treatment (12-month approval)
 
    1. All of the above requirements have been met; AND
    2. There is no evidence of relapse of the NMOSD; AND
    3. Must be dosed in accordance with the FDA label.
 
Dosage and Administration
Dosing per FDA Guidelines
 
Prior to the first dose, must have the following screening: Hepatitis B virus; quantitative serum immunoglobulins and tuberculosis.
 
Prior to every infusion:
    • Determine if there is an active infection.
    • Premedicate with a corticosteroid, an antihistamine, and an antipyretic.
 
The recommended dose is:
    • Initial dose – 300 mg intravenous infusion followed by a second 300 mg dose 2 weeks later.
    • Subsequent doses (Starting 6 months from the first infusion) – single 300 mg intravenous infusion every 6 months.
 
Inebilizumab-cdon is available as 100 mg/10 mL (10 mg/mL) solution in a single-dose vial.
 
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
 
Inebilizumab-cdon, 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, inebilizumab-cdon, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Effective September 2020 to June 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use inebilizumab-cdon for the treatment of neuromyelitis optica spectrum disorder meets primary coverage criteria that there be scientific evidence  of effectiveness in improving health outcomes when ALL of the following criteria are met:
 
Initial Treatment (6-month approval)
 
    1. The individual is > 18 years of age (Cree, 2019) AND
    2. A diagnosis of Neuromyelitis Optica or NMOSD 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)  (Wingerchuk, 2015) AND
4. A history of at least 2 relapses during the previous 24 months or at least one which had occurred within the previous 12 months (Cree, 2019). AND
5. Has an Expanded Disability Status Scale (EDSS) score of 8.0 or less (Cree, 2019) AND
6. May have use of concurrent corticosteroids limited to 20 mg per day.  AND
7. Will be ordered by or in consultation with a neurologist AND
8. Will not be given concomitantly with other biologics or IVIG (Uplinza, 2020) AND
9. Evidence of failure of, contraindication to, or intolerance of rituximab treatment (Mealy, 2014).
 
Continued Treatment (12-month approval)
 
Continuation of therapy with inebilizumab-cdon 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.
 
Dosage and Administration
Dosing per FDA Guidelines
 
Prior to the first dose, must have the following screening: Hepatitis B virus; quantitative serum immunoglobulins and tuberculosis.
 
Prior to every infusion:
    • Determine if there is an active infection.
    • Premedicate with a corticosteroid, an antihistamine, and an antipyretic.
 
The recommended dose is:
    • Initial dose – 300 mg IV followed by a second 300 mg dose 2 weeks later.
    • Subsequent doses (Starting 6 months from the first infusion) – single 300 mg IV infusion every 6 months.
 
Inebilizumab-cdon is available as 100 mg/10 mL (10 mg/mL) solution in a single-dose vial.
 
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
 
Inebilizumab-cdon does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any indication or circumstance other than those outlined above.
 
For members with contracts without primary coverage criteria, the use of Inebilizumab-cdon in any indication or condition other than listed above is considered investigational
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Effective July 2020 to August 2020
 
Policy/guidelines:
 
Effective July 1, 2020 prior approval is required for inebilizumab-cdon (Uplizna™).
 
The use of this drug 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.
 
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use for treatment of adults with inebilizumab-cdon (Uplizna™) for neuromyelitis optica spectrum disorder meets primary coverage criteria when ALL of the following criteria are met:
 
Initial Treatment (6-month approval)
 
  1. The individual is > 18 yrs of age AND
  2. A diagnosis of Neuromyelitis Optica or NMOSD as identified by documentation of at least one core clinical characteristic as follows:
    • Optic neuritis
    • Acute myelitis
    • Area postrema syndrome- episode of otherwise unexplained hiccups or nausea and vomiting
    • Acute brainstem syndrome
    • Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions
    • Symptomatic cerebral syndrome with NMOSD-typical brain lesions AND
 
3. Evidence of AQP4-IgG – Seropositive status (preferably cell based assay) AND
 
4. A history of at least 2 relapses during the previous 24 months, at least one of which had occurred within the previous 12 months. AND
 
5. Has an Expanded Disability Status Scale (EDSS) score of 8.0 or less AND
 
6. May have use of concurrent corticosteroids limited to 20 mg per day.  AND
 
7. Will be ordered by or in consultation with a neurologist AND
 
8. Will not be given concomitantly with other biologics or IVIG.
 
Continued Treatment (12-month approval)
 
Continuation of therapy with inebilizumab-cdon (Uplizna™) 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.
 
 
Dosage and Administration
  1. Prior to the first dose, must have the following screening: Hepatitis B virus; quantitative serum immunoglobulins and tuberculosis.
  2. Prior to every infusion:
    • Determine if there is an active infection.
    • Premedicate with a corticosteroid, an antihistamine, and an antipyretic.
  1. The recommended dose is:
    • Initial dose – 300 mg IV followed by a second 300 mg dose 2 weeks later.
    • Subsequent doses (Starting 6 months from the first infusion) – single 300 mg IV infusion every 6 months.
 
 
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
 
For members with contracts without primary coverage criteria, the use of Inebilizumab-cdon in any other condition than listed above is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Rationale:
A multicenter, double-blind randomized placebo-controlled phase 2/3 study was performed at 99 outpatient specialty clinics or hospitals in 25 countries.   230 adult patients, >18 yrs of age, with the diagnosis of NMOSD, were randomized to receive either inebilizumab or placebo; 174 patients received inebilizumab and 56 received placebo.  213 of the 230 patients were anti-AQP4 antibody positive, 17 were anti AQP4 antibody negative.  Of the 213 NMOSD AQP4 positive patients, 161 received inebilizumab and 52 received placebo.  Patients received inebilizumab on day 1 and 15, then every 6 months.  Use of immunosuppressants during the blinded phase of the trial were not allowed.  The primary endpoint was time to acute attack.  During the 197day study, 21 (11.2%) of 174 patients has an acute attack, versus 22 (42.3%) of 52 participants receiving placebo.  There was no evidence of benefit for patients who were anti-AQP4 negative.  The randomized control period was stopped before complete enrollment, as recommended by the independent data-monitoring committee, because of clear demonstration of efficacy.    
 
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
N-MOmentum was a prospective, multicenter, double-blind, placebo-controlled, randomized clinical trial in adults with NMOSD. sGFAP levels were measured by single-molecule arrays (SIMOA) in 1,260 serial and attack-related samples from 215 N-MOmentum participants (92% aquaporin 4-immunoglobulin G-seropositive) and in control samples (from healthy donors and patients with relapsing-remitting multiple sclerosis).
 
At baseline, 62 participants (29%) exhibited high sGFAP concentrations (≥170 pg/ml; ≥2 standard deviations above healthy donor mean concentration) and were more likely to experience an adjudicated attack than participants with lower baseline concentrations (hazard ratio [95% confidence interval], 3.09 [1.6-6.1], p = 0.001). Median (interquartile range [IQR]) concentrations increased within 1 week of an attack (baseline: 168.4, IQR = 128.9-449.7 pg/ml; attack: 2,160.1, IQR = 302.7-9,455.0 pg/ml, p = 0.0015) and correlated with attack severity (median fold change from baseline [FC], minor attacks: 1.06, IQR = 0.9-7.4; major attacks: 34.32, IQR = 8.7-107.5, p = 0.023). This attack-related increase in sGFAP occurred primarily in placebo-treated participants (FC: 20.2, IQR = 4.4-98.3, p = 0.001) and was not observed in inebilizumab-treated participants (FC: 1.1, IQR = 0.8-24.6, p > 0.05). Five participants (28%) with elevated baseline sGFAP reported neurological symptoms leading to nonadjudicated attack assessments.
 
Serum GFAP may serve as a biomarker of NMOSD activity, attack risk, and treatment effects. ANN NEUROL 2021;89:895-910. ClinicalTrials.gov NCT02200770. (Aktas O, Smith MA, Rees WA, et.al., 2021)
 
2022 Update
Efficacy and safety of inebilizumab for treatment of neuromyelitis optica spectrum disorder in adults seropositive for aquaporin-4 (AQP4)-immunoglobulin (Ig) G were demonstrated in the 28-week randomized controlled period of the N-Momentum study.
 
To assess efficacy and safety of long-term inebilizumab treatment., a post hoc analysis was performed in 75 AQP4-IgG-seropositive participants receiving inebilizumab for ⩾4 years in the randomized controlled period and open-label extension of the N-MOmentum study.
 
Eighteen attacks occurred in 13 participants during inebilizumab treatment (annualized attack rate, 0.052 attacks/person-year). Twelve attacks occurred during the first year of treatment, and two each occurred in years 2-4. Disability scores remained stable throughout ⩾4 years of treatment. Inebilizumab was well tolerated, with two (2.7%) serious treatment-emergent adverse events related to inebilizumab and no deaths. Immunoglobulin G levels decreased over time; however, correlation between severe infections and low IgG levels could not be determined because of their small numbers.
These results from the N-MOmentum study continue to support use of inebilizumab for treatment of neuromyelitis optica spectrum disorder. Furthermore, the findings suggest that efficacy of inebilizumab may be enhanced after the first year of treatment, warranting additional long-term investigation. (Rensel M, Zabeti A, Mealy MA, et.al., 2022)
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
In the double-blind, randomised, placebo-controlled, phase 2/3 N-MOmentum trial, adults aged 18 years and older with an neuromyelitis optica spectrum disorder diagnosis, Expanded Disability Status Scale score of 8·0 or less, and history of either at least one acute inflammatory attack requiring rescue therapy in the past year or two attacks requiring rescue therapy in the past 2 years, were recruited from 81 outpatient specialty clinics or hospitals in 24 countries. Eligible participants were randomly assigned (3:1), using a central interactive voice system or interactive web response system, and a permuted block randomisation scheme (block size of 4), to receive intravenous inebilizumab (300 mg) or identical placebo on days 1 and 15 of the randomised period, which lasted up to 197 days. Participants and all study staff were masked to treatment assignment. The primary endpoint of the randomised period of the trial was time to onset of adjudicated neuromyelitis optica spectrum disorder attack on or before day 197. Participants in the randomised controlled period who had an adjudicated attack, completed 197 days in the study, or were in the randomised controlled period when enrolment stopped, could voluntarily enter the open-label period. In the open-label period, participants either initiated inebilizumab if assigned placebo (receiving 300 mg on days 1 and 15 of the open-label period) or continued treatment if assigned inebilizumab (receiving 300 mg on day 1 and placebo on day 15, to maintain B-cell depletion and masking of the randomised controlled period). All participants subsequently received inebilizumab 300 mg every 6 months for a minimum of 2 years. The end-of-study analysis endpoints were time to adjudicated attack and annualised attack rate (assessed in all participants who received inebilizumab at any point during the randomised controlled period or open-label period [any inebilizumab population] and the aquaporin-4 [AQP4]-IgG seropositive subgroup [any inebilizumab-AQP4-IgG seropositive population]) and safety outcomes (in all participants who were exposed to inebilizumab, analysed as-treated). This study is registered with ClinicalTrials.gov, NCT02200770, and is now complete.
 
Between Jan 6, 2015, and Sept 24, 2018, 467 individuals were screened, 231 were randomly assigned, and 230 received at least one dose of inebilizumab (n=174) or placebo (n=56). Between May 19, 2015, and Nov 8, 2018, 165 (95%) of 174 participants in the inebilizumab group and 51 (91%) of 56 in the placebo group entered the open-label period (mean age 42·9 years [SD 12·4], 197 [91%] of 216 were female, 19 [9%] were male, 115 [53%] were White, 45 [21%] were Asian, 19 [9%] were American Indian or Alaskan Native, and 19 [9%] were Black or African American). As of data cutoff for this end of study analysis (Dec 18, 2020; median exposure 1178 days [IQR 856-1538], total exposure of 730 person-years) 225 participants formed the any inebilizumab population, and 208 (92%) participants were AQP4-IgG seropositive. Overall, 63 adjudicated neuromyelitis optica spectrum disorder attacks occurred in 47 (21%) of 225 treated participants (60 attacks occurred in 44 [21%] of 208 in the AQP4-IgG seropositive subgroup); 40 (63%) of 63 attacks occurred in 34 (15%) of 225 treated participants during the first year of treatment. Of individuals who had an adjudicated attack while receiving inebilizumab, 36 (77%) of 47 were subsequently attack-free at the end of 4 years. Annualised attack rates decreased year-on-year, with end-of-study adjusted annualised attack rates being similar in the any inebilizumab-AQP4-IgG seropositive subgroup (0·097 [95% CI 0·070-0·14]) and any inebilizumab populations (0·092 [0·067-0·13]). Overall, 208 (92%) of 225 participants who received any inebilizumab had at least one treatment-emergent adverse event, the most frequent of which were urinary tract infection (59 [26%]), nasopharyngitis (47 [21%]), and arthralgia (39 [17%]). Infection rates did not increase over 4 years. Three (1%) of 225 participants in the any inebilizumab population died during the open-label period (one each due to a CNS event of unknown cause and pneumonia, respiratory insufficiency resulting from an neuromyelitis optica spectrum disorder attack and viral pneumonia related to COVID-19), all of which were deemed to be unrelated to treatment.
 
Data from the end-of-study analysis of the N-MOmentum trial showed continued and sustained clinical benefits of long-term inebilizumab treatment in individuals with neuromyelitis optica spectrum disorder, which supports the role of inebilizumab as a CD19+ B-cell-depleting therapy in neuromyelitis optica spectrum disorder. (Cree BAC, Kim HJ, Weinshenker BG, 2024)
CPT/HCPCS:
J1823Injection, inebilizumab-cdon, 1 mg
j3490Unclassified drugs
J3590Unclassified biologics
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.
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