Inebilizumab-cdon (UpliznaTM) is a CD19-directed humanized afucosylated IgG1 monoclonal antibody produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture. The molecular weight is approximately 149 kilodaltons (kDa). Inebilizumab-cdon (Uplizna) depletes the B cells in the body that produce autoantibodies against aquaporin-4 (AQP4). This reduces the frequency of attacks and the severity of symptoms. Inebilizumab-cdon (Uplizna) was approved by the US Food and Drug Administration (FDA) for neuromyelitis optica spectrum disorder (NMOSD) on June 11, 2020. Data from the end-of-study analysis of the N-MOmentum (A Clinical Research Study of Inebilizumab in Neuromyelitis Optica Spectrum Disorders) trial showed continued and sustained clinical benefits of long-term inebilizumab treatment in individuals with NMOSD.
NEUROMYELITIS OPTICA SPECTRUM DISORDER (NMOSD)
Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system.
The safety and efficacy of inebilizumab-cdon (Uplizna) for the treatment of individuals with AQP4-IgG–positive neuromyelitis optica were evaluated in a Study 1, in which 161 individuals were exposed to inebilizumab-cdon (Uplizna) at the recommended dosage regimen during the randomized, controlled treatment period, during which 52 individuals received placebo. Subsequently, 198 individuals were exposed to inebilizumab-cdon (Uplizna) during an open-label treatment period. A total of 208 individuals in the randomized and open-label treatment periods had a total of 324 person-years of exposure to inebilizumab-cdon (Uplizna), including 165 individuals with exposure for at least 6 months and 128 with exposure for 1 year or more. The Study 1 included AQP4-IgG antibody-positive and AQP4-IgG antibody-negative individuals. During the 197-day study, the risk of an NMOSD relapse in the 161 anti-AQP4 antibody–positive individuals who were treated with inebilizumab-cdon (Uplizna) was reduced by 77% when compared to the placebo treatment group. There was no evidence of a benefit in anti-AQP4 antibody–negative individuals. The most common adverse reactions in the NMOSD clinical trial were urinary tract infection, headache, joint pain (arthralgia), nausea, and back pain.
IMMUNOGLOBULIN G4–RELATED DISEASE (IgG4-RD)
Immunoglobulin G4–related disease (IgG4-RD) is a rare, chronic autoimmune condition in which the immune system attacks healthy organs, causing inflammation, fibrosis (scarring), and often tumor-like masses that can mimic cancer, affecting organs like the pancreas, salivary glands, kidneys, and aorta. The disease is characterized by high levels of IgG4 antibodies, dense inflammation with IgG4 plasma cells, and typically responds well to steroid treatment, although early diagnosis is crucial to prevent organ damage.
The pathology of IgG4-RD is very specific and looks similar in all organs. Therefore it is considered to be analogous to systemic sarcoidosis. IgG4-RD–affected individuals are often misdiagnosed as having a malignancy because the lesions can mimic tumors, infections, or immune-mediated diseases. This disease is underdiagnosed due to the lack of a systemic approach. IgG4-RD–affected individuals usually have a good recovery after being treated with systemic glucocorticosteroids. The response to steroids is so dramatic that it is has been suggested as one diagnostic criterion for the disease.
The safety and efficacy of inebilizumab-cdon (Uplizna) for the treatment of individuals with IgG4‑related disease was evaluated in randomized, double‑blind, placebo‑controlled Phase 3 trial. The MITIGATE (A Study of Inebilizumab Efficacy and Safety in IgG4- Related Disease) trial is the first placebo‑controlled Phase 3 trial in this disease. This trial enrolled 135 adults with active IgG4‑RD, multiorgan involvement, and a recent flare requiring glucocorticoids. The study was conducted across 80 sites in 22 countries. The primary endpoint was the time to first adjudicated, investigator‑treated IgG4‑RD flare. Secondary endpoints included annualized flare rate; flare‑free, treatment‑free complete remission; glucocorticoid‑free remission; and safety and tolerability. Inebilizumab reduced risk of flare by 87% to 90% versus placebo over 52 weeks. Flares occured in 10% to 10.3% (inebilizumab) versus 59.7% to 60% (placebo). Flare‑free, treatment‑free complete remission at Week 52 was 57% (inebilizumab) versus 22% (placebo). Ninety percent of individuals receiving inebilizumab fully discontinued glucocorticoids compared with 37% for placebo.
GENERALIZED MYASTHENIA GRAVIS
Generalized myasthenia gravis (gMG) is a chronic autoimmune neuromuscular disease that causes weakness in the skeletal muscles. The muscle weakness usually worsens after periods of activity and improves after periods of rest. Muscles that control movements of the eye and eyelid, facial expression, chewing, talking, and swallowing are often involved, but those that control breathing and neck and limb movements may also be involved. This weakness is a result of an antibody-mediated, T-cell dependent, immunological attack directed at proteins in the postsynaptic membrane of the neuromuscular junction. MG has an annual incidence of about seven to 23 cases per million. It most often begins before the age of 40 in women and after age 60 in men.
The safety and efficacy of inebilizumab-cdon (Uplizna) for the treatment of individuals with gMG was studied in a late‑phase randomized, double‑blind, placebo‑controlled clinical study called MINT (A Randomized, Double-blind, Multicenter, Placebo-controlled Phase 3 Study With Open-label Period to Evaluate the Efficacy and Safety of Inebilizumab in Adults With Myasthenia Gravis), designed to determine whether a CD19‑targeting monoclonal antibody can meaningfully improve symptoms and disease control in people living with gMG. Participants were adults with confirmed generalized MG who carried one of the two major MG‑associated autoantibodies: acetylcholine receptor (AChR) antibodies or muscle‑specific kinase (MuSK) antibodies.
Participants were randomly assigned in equal numbers to receive either the investigational therapy or placebo. Dosing occurred on a fixed schedule and differed slightly depending on antibody subtype. A key feature of the study was a structured glucocorticoid taper, which began early in treatment. Individuals who entered on prednisone or an equivalent medication were gradually reduced to a low daily dose by the middle of the trial. This allowed investigators to see whether the study medication could maintain disease control despite decreasing steroid exposure.
The primary end point was change in Myasthenia Gravis Activities of Daily Living (MG‑ADL) at Week 26, assessed across the entire antibody‑positive participant population. Secondary end points were changes in Quantitative Myasthenia Gravis (QMG) score, another widely accepted measure of MG severity, individual assessments of treatment response within AChR‑positive and MuSK‑positive subgroups and additional measures related to function, strength, and disease stability. Overall adverse events (AE) were similar between groups (approximately 81% vs 73%), suggesting no major increase in overall adverse events with inebilizumab. Common AEs (>10%) included headache, and mild infections (including COVID‑19) were most frequent in the active arm. Serious AEs were numerically lower in the inebilizumab group (8.4%) compared with that in the placebo group (13.4%); there was no anaphylaxis or severe hypersensitivity.
OFF-LABEL INDICATION
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
