Inebilizumab-cdon (Uplizna)

Number: 0975

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses inebilizumab-cdon (Uplizna) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification

Precertification of inebilizumab-cdon (Uplizna) is required of all Aetna participating providers and members in applicable plan designs. For precertification of inebilizumab-cdon (Uplizna) call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification. 

Note: Site of Care Utilization Management Policy applies. For information on site of service for inebilizumab-cdon (Uplizna) infusions, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

1. Criteria for Initial Approval

   Aetna considers inebilizumab-cdon (Uplizna) medically necessary for the treatment of neuromyelitis optica spectrum disorder (NMOSD) when all of the following criteria are met:
   
   
   1. Member is anti-aquaporin-4 (AQPR) antibody positive; and
   2. Member exhibits one of the following core clinical characteristics of NMOSD:
      
      
      1. Optic neuritis; or
      2. Acute myelitis; or
      3. Area postrema syndrome (episode of otherwise unexplained hiccups or nausea and vomiting); or
      4. Acute brainstem syndrome; or
      5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic magnetic resonance imaging (MRI) lesions; or
      6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions; and
   3. The member will not receive the requested medication concomitantly with other biologics for the treatment of NMOSD.

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

2. Continuation of Therapy

   Aetna considers continuation of inebilizumab-cdon (Uplizna) therapy medically necessary when all of the following criteria are met:
   
   
   1. There is no evidence of unacceptable toxicity or disease progression while on the current regimen; and
   2. The member demonstrates a positive response to therapy (e.g., reduction in number of relapses); and
   3. The member will not receive the requested medication concomitantly with other biologics for the treatment of NMOSD.

3. Related Polices

   • CPB 0314 - Rituximab
   • CPB 0807 - Eculizumab (Soliris)
   • CPB 0946 - Ravulizumab-cwvz (Ultomiris)

Dosage and Administration

Inebilizumab-cdon is available as Uplizna for injection as 100 mg/10 mL solution in a single-dose vial, and must be diluted in 250 mL of 0.9% Sodium Chloride Injection, USP prior to administration.

Uplizna is administered as an intravenous (IV) infusion titrated to completion, approximately 90 minutes. The recommended dosage is:

• Initial dose: 300 mg IV infusion followed 2 weeks later by a second 300 mg IV infusion;
• Subsequent doses (starting 6 months from the first infusion): single 300 mg IV infusion every 6 months.

Note: Hepatitis B virus, quantitative serum immunoglobulins, and tuberculosis screening are required before the first dose. Prior to every infusion, determine if there is an active infection, and premedicate with a corticosteroid, an antihistamine, and an antipyretic. Monitor individuals closely during the infusion and for at least one hour after completion of the infusion.

Source: Horizon Therapeutics USA, 2021

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96365 - 96368	Intravenous infusion administration
HCPCS codes covered if selection criteria are met:
J1823	Injection, inebilizumab-cdon, 1 mg
ICD-10 codes covered if selection criteria are met:
G36.0	Neuromyelitis optica [Devic]

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Background

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

• Uplizna is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

Inebilizumab-cdon, a CD19-directed cytolytic antibody, is branded as Uplizna (Horizon Therapeutics USA, Inc, formerly Viela Bio, Inc.). Inebilizumab, the active ingredient in Uplizna, is a genetically engineered humanized monoclonal antibody that binds to the B cell specific surface antigen cluster of differentiation (CD19) resulting in the depletion of B cells. Inebilizumab depletes antibody-secreting plasmablasts and some plasma cells, which are generally CD19 positive and CD20 negative (MedImmune, 2020). B cells are believed to play a critical role in neuromyelitis optica spectrum disorders (NMOSD). The safety and efficacy of inebilizumab was evaluated in a clinical trial which led to the U.S. Food and Drug Administration (FDA) approval of Uplizna (inebilizumab-cdon) for the treatment of NMOSD, a rare, relapsing, autoimmune, inflammatory disease of the central nervous system (CNS) that causes blindness and paralysis. The precise mechanism by which Uplizna (inebilizumab-cdon) exerts its therapeutic effects in NMOSD is unknown but is presumed to involve the binding to CD19. Following cell surface binding to B lymphocytes, inebilizumab-cdon results in antibody-dependent cellular cytolysis.

Neuromyelitis optica spectrum disorder (NMOSD), previously known as Devic disease, is a rare autoimmune inflammatory disorder of the central nervous system characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting optic nerves and the spinal cord leading to vision loss and paralysis. Approximately 50% of individuals with NMOSD have permanent visual impairment and paralysis caused by NMOSD attacks (FDA, 2020). The aquaporin-4 (AQP4)-IgG serum autoantibody, also known as NMO-IgG, is a specific biomarker for NMOSD. The AQP4 receptor is the target antigen of NMO-IgG, which has a direct role in the pathogenesis of NMOSD (Glisson, 2022). Binding of the anti-AQP4 antibody appears to activate other components of the immune system, causing inflammation and damage to the central nervous system. According to the National Institutes of Health, women are more often affected by NMOSD than men and African Americans are at greater risk of the disease than are Caucasians. Estimates vary, but NMOSD is thought to impact approximately 4,000 to 8,000 patients in the United States (FDA, 2020). In a 2022 cross-sectional study by Briggs and Shaia (2024), there were 1772 NMOSD patients among 25,743,039 patients for a prevalence of 6.88 per 100,000 in the United States.

On June 11, 2020, the FDA granted approval for Uplizna (inebilizumab-cdon) injection for intravenous use for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. FDA approval was based on the N-MOmentum trial.

Cree et al. (2019) conducted a multicenter, double-blind, randomized placebo-controlled phase 2/3 study (N-Momentum) to assess the efficacy and safety of inebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk of attacks and disability in NMOSD. The study included 230 participants diagnosed with NMOSD who were at least 18 years of age or older and had a history of at least one attack requiring rescue therapy in the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening. Exclusions included history of hepatitis B and/or C at screening, and previously treated with immunosuppressant therapies within an interval specified for each such therapy. In the trial, 213 of the 230 patients had antibodies against AQP4 (anti-AQP4 antibody positive). Participants were randomly allocated (3:1) to 300 mg intravenous inebilizumab or placebo, administered on days 1 and 15. Of the 230 participants who were randomly assigned to treatment and dosed, 174 participants received inebilizumab and 56 received placebo. However, of the 213 participants that were anti-AQP4 antibody positive, 161 were randomized to receive treatment with inebilizumab, and 52 were randomized to receive placebo (FDA, 2020). The primary endpoint was time to onset of an NMOSD attack. Efficacy endpoints were assessed in all randomly allocated participants who received at least one dose of study intervention, and safety endpoints were assessed in the as-treated population. The authors found that 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo (p < 0·0001). Adverse events occurred in 125 (72%) of 174 participants receiving inebilizumab and 41 (73%) of 56 participants receiving placebo. Serious adverse events occurred in eight (5%) of 174 participants receiving inebilizumab and five (9%) of 56 participants receiving placebo. In the anti-AQP4 antibody positive population there was a 77.3% relative reduction (p < 0.0001). There was no evidence of a benefit in participants who were anti-AQP4 antibody negative (FDA, 2020; Viela Bio, 2021). Cree and colleagues concluded that compared with placebo, inebilizumab reduced the risk of an NMOSD attack, and has the potential application as an evidence-based treatment for patients with NMOSD.

According to the Prescribing Information, Uplizna is contraindicated in persons who have an active hepatitis B infection, active or untreated latent tuberculosis (TB), or have history of a life-threatening infusion reaction to inebilizumab. 

Labeled warnings and precautions include risk for infusion reaction, which can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash, or other signs or symptoms. During the randomized clinical trial period, infusion reactions were observed with the first course of Uplizna in 9.3% of NMOSD patients. Infusion reactions were most common with the first infusion but were also observed
during subsequent infusions. Moreover, an increased risk of infections has been observed with other B-cell-depleting therapies.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no confirmed cases of PML were identified in Uplizna clinical trials, JC virus infection resulting in PML has been observed in patients treated with other B-cell-depleting antibodies and other therapies that affect immune competence. In Uplizna clinical trials one subject died following the development of new brain lesions for which a definitive diagnosis could not be established, though the differential diagnosis included an atypical NMOSD relapse, PML, or acute disseminated encephalomyelitis.

Risk of hepatitis B virus (HBV) reactivation has been observed with other B-cell-depleting antibodies. There have been no cases of HBV reactivation in patients treated with Uplizna; however, patients with chronic HBV infection were excluded from clinical trials. 

Uplizna has not been studied in combination with other immunosuppressants. Concomitant usage of Uplizna with immunosuppressant drugs, including systemic corticosteroids, may increase the risk of infection. Risk of additive immune system effects must be considered when co-administering immunosuppressive therapies with Uplizna.

Based on animal data, Uplizna can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to UPLIZNA even after B-cell repletion. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other B-cell depleting antibodies during pregnancy. 

The most common infections reported by Uplizna-treated patients in the randomized and open-label clinical trial periods included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%), and influenza (7%).

The most common adverse reactions (at least 10% of patients treated with Uplizna and greater than placebo) were urinary tract infection and arthralgia.

Safety and effectiveness in pediatric have not been established. Clinical studies of Uplizna did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

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References