Inebilizumab-cdon (Uplizna)

Number: 0975

Table Of Contents

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

---

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 treatment of the following indications when criteria are met:

   1. 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;

   2. Immunoglobulin G4-related disease (IgG4-RD)  when all of the following criteria are met:

      1. Member has a clinical diagnosis of IgG4-RD confirmed by either of the following (see Appendix A for evaluations and characteristic organs to confirm diagnosis):

         1. Clinical or radiologic involvement of a characteristic organ; or
         2. Pathologic evidence from a characteristic organ; and
      2. Alternative causes of member’s clinical signs and symptoms have been evaluated and ruled out (see Appendix B for common mimickers of IgG4-RD); and
      3. Member is experiencing an IgG4-RD flare that requires initiation or continuation of glucocorticoid treatment (within the past 4 weeks); and
      4. Member has a history of IgG4-RD affecting at least 2 organs/sites at any time (does not need to occur currently) in the course of IgG4-RD.

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

2. Continuation of Therapy

   Aetna considers continuation of inebilizumab-cdon (Uplizna) therapy medically necessary for the following indications when criteria are met:

   1. Neuromyelitis optica spectrum disorder (NMOSD) 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;

   2. Immunoglobulin G4-related disease (IgG4-RD) when both 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 IgG4-RD flares).

3. Related Polices

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

Dosage and Administration

Uplizna is supplied in a single-dose vial containing 100 mg of inebilizumab-cdon in 10 mL solution 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 screenings 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, 2025

---

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
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]
D89.84	IgG4-related disease

---

Background

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

• Treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive;
• Treatment of immunoglobulin G4-related disease (IgG4-RD) in adult patients.

Inebilizumab-cdon, a CD19-directed cytolytic antibody, is branded as Uplizna (Horizon Therapeutics USA, Inc, formerly Viela Bio, Inc.). Inebilizumab 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. However, the precise mechanism by which inebilizumab-cdon exerts its therapeutic effects in conditions such as neuromyelitis optica spectrum disorder (NMOSD) and immunoglobulin G4-related disease (IgG4-RD) is unknown but is presumed to involve binding to CD19. Following cell surface binding to B lymphocytes, inebilizumab-cdon results in antibody-dependent cellular cytolysis.

Uplizna is contraindicated in persons with previous life-threatening reaction from Uplizna infusion, have active hepatitis B infection, and/or have active or untreated latent tuberculosis (TB).

Labeled warnings and precautions include risk for infusion reaction (including anaphylaxis), infections, and risk to immunoglobulin levels. Symptoms of an infusion reaction may include headache, nausea, somnolence, dyspnea, fever, myalgia, rash, or palpitations. In clinical trials, infusion reactions were observed with the first course of Uplizna in 9.3% of NMOSD patients and 7.4% of IgG4-RD patients. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions. In clinical trials, the most common infections reported by Uplizna-treated patients for NMOSD included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%), and influenza (7%); and for IgG4-RD patients were upper respiratory tract infection (11%), nasopharyngitis (10%), urinary tract infection (9%), and influenza (6%).

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. 

Patients should be evaluated for tuberculosis (TB) risk factors and tested for latent infection prior to initiating Uplizna. 

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.

There may be a progressive and prolonged hypogammaglobulinemia or decline in the levels of total and individual immunoglobulins such as immunoglobulins G and M (IgG and IgM) with continued Uplizna treatment. Thus, monitoring levels of quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections, and until B-cell repletion after discontinuation of therapy, is recommended. 

Uplizna may cause fetal harm 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. Thus, females of reproductive potential should be advised of the potential risk to a fetus and to use an effective method of contraception during treatment and for 6 months after stopping Uplizna. 

The most common adverse reactions in NMOSD (at least 10% of patients treated with Uplizna and greater than placebo) were urinary tract infection and arthralgia. The most common adverse reactions in IgG4-RD (at least 10% of patients treated with Uplizna and greater than placebo) were urinary tract infections and lymphopenia. 

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.

Neuromyelitis Optica Spectrum Disorder (NMOSD)

Neuromyelitis optica spectrum disorder (NMOSD), previously known as Devic disease, is a rare autoimmune inflammatory disorder of the central nervous system (CNS) 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 intravenous use of Uplizna (inebilizumab-cdon) 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 (NCT02200770) that found that inebilizumab reduced the risk of an NMOSD attack in persons anti-AQP4 antibody positive. 

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.

Immunoglobulin G4-Related Disease (IgG4-RD)

Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder that often manifests with tumor-like masses and/or painless enlargement of multiple organs. It is characterized by periods of remission and unpredictable disease flares. IgG4-RD can cause permanent organ damage with or without the presence of symptoms. Symptoms depend on which organs are affected. Moreover, the disease mimics other diseases due to the heterogeneous and unpredictable inflammatory flares that can occur. Thus, diagnosis generally requires biopsy. Over time, IgG4-RD can affect virtually any organ system. Corticosteroids are considered first-line therapy. Although nearly all patients with IgG4-RD respond to glucocorticoids, approximately 40% of those fail to achieve complete remission or relapse within one year. In IgG4-RD, CD19-expressing (CD19+) B cells are thought to drive inflammatory and fibrotic processes and interact with other immune cells that contribute to disease activity.

The prevalence of IgG4-RD is estimated at 20,000 people in the United States, although the number of patients with IgG4-RD is difficult to determine based on limited epidemiology data. The typical age of onset of IgG4-RD is between 50 and 70 years old and, unlike many other immune-mediated diseases, IgG4-RD is more likely to occur in men than women (Amgen, 2025; Stone et al, 2025).

In April 2025, the U.S. FDA approved the use of inebilizumab-cdon, branded as Uplizna (Horizon Therapeutics USA, Inc), for the treatment of IgG4-RD in adults. Approval is supported by data from the MITIGATE trial which demonstrated the potential of Uplizna to decrease disease activity by reducing flares in patients, while maintaining its efficacy and established safety profile.

The MITIGATE trial (NCT04540497) is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase 3 trial that evaluated the efficacy and safety of inebilizumab-cdon compared to placebo in reducing the risk of flares in adults with IgG4-RD. The primary endpoint was time to first treated and adjudicated IgG4-RD flare. The three key secondary endpoints were annualized flare rate; flare-free, treatment-free complete remission; and flare-free, corticosteroid-free complete remission. The MITIGATE trial also includes an optional three-year open-label treatment period and a safety follow-up period after inebilizumab-cdon discontinuation of up to two years.

Stone and colleagues (2025) state that inebilizumab targets and depletes CD19+ B cells which may be effective for treating patients with IgG4-related disease. In the MITIGATE trial, a total of 135 participants with IgG4-related disease underwent randomization in a 1:1 ratio to receive inebilizumab (n=68; 300-mg intravenous infusions on days 1 and 15 and week 26) or placebo (n=67) for a 52-week treatment period. Participants in both groups received identical glucocorticoid tapers. Glucocorticoids were allowed to treat disease flares, but background immunosuppressants were not permitted. The primary end point was the first treated, adjudicated disease flare during the treatment period, assessed in a time-to-event analysis. Disease flare was defined as new/worsening signs or symptoms that were positively adjudicated and warranted treatment by the investigator. All potential flares were assessed by the investigator and subsequently reviewed by a blinded, independent, adjudication committee, who determined whether the flare met one or more of the protocol-defined, organ-specific flare diagnostic criteria. Key secondary end points were the annualized flare rate and treatment-free and glucocorticoid-free complete remission. The investigators found that treatment with inebilizumab reduced flare risk; 7 participants (10%) in the inebilizumab group had at least one flare, as compared with 40 participants (60%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.06 to 0.28; P<0.001). The annualized flare rate was lower with inebilizumab than with placebo (rate ratio, 0.14; 95% CI, 0.06 to 0.31; P<0.001). More participants in the inebilizumab group than in the placebo group had flare-free, treatment-free complete remission (odds ratio, 4.68; 95% CI, 2.21 to 9.91; P<0.001) and flare-free, glucocorticoid-free complete remission (odds ratio, 4.96; 95% CI, 2.34 to 10.52; P<0.001). Serious adverse events occurred during the treatment period in 12 of the participants (18%) who received inebilizumab and 6 of the participants (9%) who received placebo. The investigators concluded that inebilizumab reduced the risk of flares of IgG4-related disease and increased the likelihood of flare-free complete remission at 1 year, which they report, confirms the role of CD19-targeted B-cell depletion as a potential treatment for IgG4-related disease.

MITIGATE trial inclusion criteria required the following:

• Participants to be 18 years of age or older
• Have a clinical diagnosis of IgG-RD
• Fulfillment of the 2019 ACR/EULAR classification criteria
• Experiencing (or recently experienced) an IgG4-RD flare that requires initiation or continuation of glucocorticoid (GC) treatment at the time of informed consent.
• IgG4-RD affecting at least 2 organs/sites at any time in the course of IgG4-RD.

Key exclusion criteria were:

• History of solid organ or cell-based transplantation or known immunodeficiency disorder
• Active malignancy or history of malignancy that was active within the last 10 years (some specific situations for cervical, skin or prostate cancer are acceptable)
• Receipt of any biologic B cell-depleting therapy or non-depleting B-cell-directed therapy in the 6 months prior to screening
• Receipt of non-biologic disease-modifying antirheumatic drugs (DMARD) or immunosuppressive agent other than GCs within 4 weeks prior to screening
• Active tuberculosis or high risk for tuberculosis; hepatitis C infection in absence of curative treatment; evidence of hepatitis B infection
• Receipt of live vaccine or live therapeutic infectious agent within 2 weeks prior to screening
  Estimated glomerular filtration rate < 30 mL/min/1.73 m^2.

Data from the MITIGATE trial revealed an 87% reduction in the risk of IgG4-RD flare compared to placebo (Hazard Ratio 0.13, p<0.001) during the 52-week placebo-controlled period; 10.3% (7 of 68) of participants receiving inebilizumab experienced a flare compared to 59.7% (40 of 67) of participants receiving placebo. A reduction in annualized flare rate for treated and adjudication committee-determined flares during the placebo-controlled period; 0.10 for participants receiving inebilizumab compared to 0.71 for participants receiving placebo (p<0.001). In addition, 57.4% (39 of 68) of participants receiving inebilizumab achieved flare-free, treatment-free, and complete remission at Week 52 compared to 22.4% (15 of 67) of participants receiving placebo (p<0.001). Moreover, 58.8% (40 of 68) of participants receiving inebilizumab achieved flare-free, corticosteroid-free, and complete remission at Week 52 compared to 22.4% (15 of 67) of participants receiving placebo (p<0.001).

In summary, the FDA granted Breakthrough Therapy Designation for the use of inebilizumab-cdon, branded as Uplizna, as a safe and beneficial medication for the treatment of adults with IgG4-RD.

---

Appendix

Appendix A: Adapted from the 2020 Revised Comprehensive Diagnostic Criteria for IgG4-RD and the 2019 ACR/EULAR Classification Criteria for IgG4-RD

Clinical or radiological features:

• One or more organs show diffuse or localized swelling or a mass or nodule characteristic of IgG4-RD. In single organ involvement, lymph node swelling is omitted.
• Note: Nearly any organ can be affected, but characteristic organs involved include:
  
  
  • Pancreas
  • Salivary gland
  • Bile ducts
  • Orbits
  • Kidney
  • Lung
  • Aorta
  • Retroperitoneum
  • Pachymeninges
  • Thyroid gland (Riedel's thyroiditis).
    
    

• Pathological diagnosis (positivity for two of the following three criteria):

  • Dense lymphocyte and plasma cell infiltration with fibrosis
  • Ratio of IgG4-positive plasma cells /IgG-positive cells greater than 40% and the number of IgG4-positive plasma cells greater than 10 per high powered field
  • Typical tissue fibrosis, particularly storiform fibrosis, or obliterative phlebitis.

Appendix B: Common Mimickers of IgG4-RD

• Malignancy
• Vasculitis
• Sjogren's syndrome
• Primary granulomatous inflammation (including sarcoidosis)
• Infection
• Multicentric Castleman's disease
• Erdheim-Chester disease
• Crohn's disease or ulcerative colitis (if only pancreatobiliary disease is present)
• Hashimoto thyroiditis (if only the thyroid is affected)

Source: Wallace et al, 2020; Umehara et al, 2021

---

References