Introduction

Inebilizumab is a monoclonal antibody to CD19 that is used to treat adults with neuromyelitis optica spectrum disorder accompanied by an autoantibody to aquaporin-4. Inebilizumab therapy is associated with an increased risk of infections and possibly reactivation of hepatitis B and tuberculosis, but it has not been associated with serum aminotransferase elevations during therapy or to instances of clinically apparent liver injury.

Background

Inebilizumab (in eb” i liz’ ue mab) is a humanized, cytolytic monoclonal antibody to CD19 that is used to treat adults with neuromyelitis optica spectrum disorder (NMOSD), a severe neurologic disease marked by bilateral optic neuritis and transverse myelitis that is accompanied by a distinctive autoantibody to aquaporin-4 (antiAQP4). In many ways, NMOSD resembles multiple sclerosis (MS) and is similarly marked by spontaneous relapses and remissions. Yet NMOSD differs from MS by the absence of typical brain findings on magnetic resonance imaging and by the presence of antiAQP4, a possibly pathogenic antibody. Inebilizumab dramatically lowers peripheral B cells, and chronic therapy is effective in lowering immunoglobulin levels and reducing relapses of NMSOD. Inebilizumab was approved for treatment of adults with neuromyelitis optica spectrum disorder positive for anti-AQP4 in the United States in 2020. Inebilizumab is available in solution in single use vials of 100 mg/10mL under the brand name Uplizna. The recommended dose regimen is 300 mg by intravenous infusion at time 0 and 2 weeks later, followed by every 6 months. Patients should be screened for hepatitis B and tuberculous before starting therapy and should have serum immunoglobulin levels measured and be given any needed live viral vaccines beforehand. Premedication with acetaminophen, antihistamines, or corticosteroids is recommended. In prelicensure trials, common adverse events included infusion reactions, reduction in immunoglobulin levels, arthralgias, and urinary tract infections. Serious adverse events associated with inebilizumab therapy include severe infections, hypersensitivity reactions, and embryo-fetal toxicity. Because it lowers peripheral B cells, inebilizumab may cause reactivation of tuberculosis, hepatitis B, and herpes virus infections, and possibly lead to progressive multifocal leukoencephalitis.

Hepatotoxicity

In registration controlled trials, serum ALT elevations occurred in 21% of inebilizumab vs 23% of placebo recipients and were above 3 times the upper limit of normal (ULN) in 5 of 161 (3.1%) on inebilizumab vs only 1 of 51 (2%) on placebo. One patient receiving inebilizumab developed acute cholangitis with ALT and AST elevations above 5 times ULN but without jaundice and responding rapidly to antibiotics and biliary drainage. Since the approval of inebilizumab in 2020, there have been no case reports of clinically apparent liver injury attributed to its use. Monoclonal antibodies to CD19 have been used for other indications and similarly have been free of liver injury. These B cell directed monoclonal antibodies, however, are considered possible causes of reactivation of hepatitis B and prescreening for hepatitis B status is often recommended.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The causes of the mild liver test abnormalities during inebilizumab therapy are not clearly known but appear to be related to the underlying condition or comorbidities such as nonalcoholic fatty liver disease or gallstone disease. Inebilizumab can cause hypersensitivity reactions including urticaria and rash, and liver injury might be a part of the immunoallergic reaction. Cases of reactivation of hepatitis B were not observed during prelicensure studies and should not occur with adequate prescreening and prophylaxis against reactivation.

Outcome and Management

The product label for inebilizumab does not recommend monitoring of routine liver tests during therapy but does recommend screening for hepatitis B before starting therapy and obtaining advice from a hepatologist regarding prophylaxis. Nevertheless, de novo elevations of serum aminotransferase levels above 5 times the ULN or baseline values should lead to temporary discontinuation and evaluation for other possible causes of liver injury, restarting therapy only when values return to normal or near normal and with careful subsequent monitoring.

Drug Class: Neurological Disease Agents; Monoclonal Antibodies