Cracking the code on rare immune-mediated diseases has been a challenge for the scientific community. This highly complex area of human biology encompasses a range of diseases caused by immune dysregulation that can have a devastating impact on people’s lives. Because these diseases manifest very differently in people, those affected often suffer from lengthy odysseys to reach a proper diagnosis and ultimately have few therapeutic options. Only in recent years have researchers made real progress in understanding the pathways that drive these diseases, which has in turn spurred traction in therapeutic innovation.
Research dedicated to the function of B cells – the important immune cells that produce infection-fighting antibodies – found that they can cause a cascade of faulty immune reactions, leading to inflammation when dysregulated. This inspired the development of UPLIZNA® (inebilizumab-cdon), an engineered antibody therapy designed to precisely bind to and target B cells expressing the protein marker CD19+, including plasmablasts and some plasma cells. While the precise mechanism by which UPLIZNA exerts its therapeutic effects is unknown, by targeting the CD19+ B cells, the therapy aims to reduce inflammation contributing to the immune dysfunction in affected individuals.
Robust data has demonstrated the benefits of this targeted mechanism in several diseases, culminating in UPLIZNA’s recent U.S. FDA approval for treatment of adults living a with rare and chronic immune-mediated condition called IgG4-related disease (IgG4-RD). UPLIZNA is now the first-ever FDA-approved therapy for this debilitating disease. UPLIZNA is contraindicated in patients with: a history of life-threatening infusion reaction to UPLIZNA, active hepatitis B infection, or active or untreated latent tuberculosis.
IgG4-RD “mimics” other diseases due to the heterogeneous and unpredictable inflammatory flares that can occur and lead to permanent damage in essentially any organ system – and often in multiple organs at the same time. Awareness of how organ damage manifests is critically important in the timely diagnosis of IgG4-RD. Most health professionals are unfamiliar with this disease, causing many affected individuals to experience long diagnostic journeys, leaving them with few answers or real options. Physicians have historically managed IgG4-RD with steroids, which can carry a range of harmful side effects, and with biologic agents not approved for use in IgG4-RD.
Only in the last two decades have researchers uncovered that IgG4-RD flares are due to aberrant activity of B cells, which are characterized by overproduction of IgG4 and drive inflammation and fibrosis through several distinct mechanisms.
“B cell-focused innovation is changing the story for a disease that has had so little attention or awareness until now. Because of our crystallized understanding of the pathways driving the disease, we felt confident that the B cell-depleting mechanism of UPLIZNA would provide a viable option for our IgG4-RD patients, and the Phase 3 MITIGATE study demonstrated just that,” said Dr. John Stone, MITIGATE principal investigator, and a professor of medicine at Harvard Medical School and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital.
IgG4-RD is the second approved indication for UPLIZNA, following its approval in 2020 for adults with AQP4-IgG+ neuromyelitis optica spectrum disorder.
“We are very proud of the journey that has led us to this approval for UPLIZNA, and deeply appreciate the physicians, patients, and families who have supported these efforts. This day is really a moment of hope for the IgG4-RD community,” said Daniel Cimbora, PhD, Senior Scientific Director at Amgen. “We hope to use the positive data from the MITIGATE trial and the recent FDA approval to build awareness and understanding of IgG4-RD among patients and healthcare providers, shortening diagnostic journeys and giving patients an effective treatment option.”
UPLIZNA® (inebilizumab-cdon) U.S. INDICATION
INDICATIONS
UPLIZNA® (inebilizumab-cdon) is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.
UPLIZNA® is indicated for the treatment of Immunoglobulin G4-related disease (IgG4-RD) in adult patients.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
UPLIZNA® (inebilizumab-cdon) is contraindicated in patients with a history of a life-threatening infusion reaction to UPLIZNA, active hepatitis B infection, or active or untreated latent tuberculosis.
WARNINGS AND PRECAUTIONS
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Infusion Reactions: Can cause infusion reactions, including anaphylaxis. Symptoms can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash, or palpitations. During the randomized clinical trial period (RCP), infusion reactions were observed with the first course of UPLIZNA in 9.3% of NMOSD patients. Infusion reactions of UPLIZNA were observed in 7.4% of IgG4-RD patients during the RCP. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions.
Administer pre-medication with a corticosteroid, an antihistamine, and an antipyretic. For life-threatening infusion reactions, immediately and permanently stop UPLIZNA and administer appropriate supportive treatment. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.
Infections: An increased risk of infections has been observed with other B-cell depleting therapies. The most common infections reported by UPLIZNA-treated patients in the NMOSD RCP and open-label clinical trial periods were urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%), and influenza (7%). In the IgG4-RD RCP and open-label period, the most common infections reported by UPLIZNA-treated patients were upper respiratory tract infection (11%), nasopharyngitis (10%), urinary tract infection (9%), and influenza (6%). Delay UPLIZNA administration in patients with an active infection until the infection is resolved.
Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants: UPLIZNA has not been studied in combination with other immunosuppressants. If combining UPLIZNA with another immunosuppressive therapy, consider the potential for increased immunosuppressive effects.
Hepatitis B Virus (HBV) Reactivation: Risk of HBV reactivation has been observed with other B-cell depleting antibodies. There have been no cases of HBV reactivation in patients treated with UPLIZNA, but patients with chronic HBV infection were excluded from clinical trials. Perform HBV screening in all patients before initiation of treatment. Do not administer to patients with active hepatitis. For patients who are chronic carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment.
Progressive Multifocal Leukoencephalopathy (PML): 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. At the first sign or symptom suggestive of PML, withhold UPLIZNA and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
Tuberculosis
Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating UPLIZNA. Consider anti-tuberculosis therapy prior to initiation of UPLIZNA in patients with a history of latent active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consult infectious disease experts regarding whether initiating anti-tuberculosis therapy is appropriate before starting treatment.
Vaccinations
Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of UPLIZNA. The safety of immunization with live or live-attenuated vaccines following UPLIZNA therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion.
Vaccination of Infants Born to Mothers Treated with UPLIZNA During Pregnancy
In infants of mothers exposed to UPLIZNA during pregnancy, do not administer live or live-attenuated vaccines before confirming recovery of B-cell counts in the infant. Depletion of B-cells in these exposed infants may increase the risks from live or live-attenuated vaccines. Non-live vaccines, as indicated, may be administered prior to recovery from B-cell and immunoglobulin level depletion, but consultation with a qualified specialist should be considered to assess whether a protective immune response was mounted.
Reductions in Immunoglobulins: 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. Monitor the levels of quantitative serum immunoglobulins during treatment with UPLIZNA, especially in patients with opportunistic or recurrent infections, and until B-cell repletion after discontinuation of therapy. Consider discontinuing UPLIZNA therapy if a patient with low immunoglobulin G or M develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.
Fetal Risk: 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. Advise females of reproductive potential to use effective contraception while receiving UPLIZNA and for at least 6 months after the last dose.
ADVERSE REACTIONS
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.
Please see UPLIZNA® full Prescribing Information.
