Q: What is the clinical indication for inebilizumab?
A. In June 2020, inebilizumab was FDA approved for the treatment of adults with anti-aquaporin 4 (AQP4) antibody positive neuromyelitis optica spectrum disorder (NMOSD). It was the second medication approved for the treatment of NMOSD, after the June 2019 approval of eculizumab and before the August 2020 approval of satralizumab.
Q: What is the mechanism of action of inebilizumab?
A. Inebilizumab is a humanized monoclonal antibody which targets the CD-19 surface antigen on B-cells and depletes them via antibody-dependent cell mediated cytotoxicity. Compared to anti-CD20 monoclonal antibodies, which recognize and deplete a small subset of CD20-expressing T cells along with B lymphocytes, anti-CD19 antibodies deplete a wider range of exclusively B lymphocytes, including pro-B cells and mature plasma cells. Evidence suggests that NMOSD is a predominantly B-cell mediated disorder caused by pathological auto-antibody production, pro-inflammatory cytokine secretions, and B-cell antigen presentation.
Q: What did the clinical trials of inebilizumab show?
A. The N-MOmentum trial was a phase 3, randomized, double-blind placebo controlled trial with a primary endpoint of time to NMOSD attack. At the time of the start of the clinical trial, there was no FDA-approved therapies for NMOSD and this study was the first large, randomized controlled trial to show superiority over placebo in terms of the risk of an NMOSD attack, disability worsening, MRI lesion activity, and disease-related hospitalizations. This study was based on a retrospective, observational evidence of clinical benefit of anti-CD20 B-cell depleting therapies. In preclinical models and phase 1 studies in systemic sclerosis and multiple sclerosis, inebilizumab depleted CD19B-cells with an acceptable safety profile.
Patients were randomized 3:1 to inebilizumab or placebo. Secondary endpoints included worsening of EDSS from baseline, change in low-contrast visual acuity score from baseline, total number of active MRI lesions, and number of NMOSD-related inpatient hospitalizations. Participants included adults with the diagnosis of NMOSD with active disease, who were either AQP4-IgG positive, or negative and meeting the Wingerchuck criteria for the diagnosis of NMOSD. 92% and 93% of participants were AQP4 IgG positive in the inebilizumab and placebo groups respectively, with 7 of 17 seronegative patients testing positive for MOG antibodies. Participants were not allowed to be on other immunosuppressant therapy during the trial, but due to the possible risk of relapse with initiating B-cell therapy they were given an oral corticosteroids taper. They were followed for up to 6 months or until the occurrence of an attack. After the randomized controlled period, patients were eligible to enroll in the observational phase where everyone was continued on inebilizumab.
The study was stopped early due to clear demonstration of efficacy, with 12% of inebilizumab treated participants experiencing a relapse versus 39% of placebo treated participants (HR 0.272, 95% CI 0.150, 0.496). In the AQP-4 IgG positive subgroup, 11% of inebilizumab treated participants experienced a relapse versus 42% of the placebo treated participants (HR 0.227, 95% CI 0.121, 0.423). Among the 17 seronegative participants, 3 attacks occurred which were all in the inebilizumab group, and no attacks in the 4 seronegative participants in the placebo group. Due to this, the efficacy could not be interpreted in the AQP-4 IgG seronegative cohort.
Additionally, fewer participants had EDSS worsening in the inebilizumab group, as well as fewer active MRI lesions and hospitalizations. The rates of adverse events and serious adverse events were similar between inebilizumab and placebo treated participants.
Q: How is inebilizumab administered?
A: Inebilizumab is given by IV infusion. The dosing schedule is 300mg on day 1 and 300mg two weeks later, then subsequent 300mg doses are given once every six months (starting 6 months from the first 300mg infusion). The infusion is given over 90 minutes, starting at a rate of 42mL/hour for the first 30 minutes, then increased to 125mL/hour for the next 30 minutes, then 333mL/hour for the remainder of the infusion.
Prior to infusion, premedication with an antihistamine such as diphenhydramine 25mg to 50mg orally, an antipyretic such as acetaminophen 500mg-650mg orally, and a corticosteroid such as methylprednisolone 80mg-125mg IV given 30-60 minutes prior to the infusion to reduce the risk of infusion related reactions.
Q: What are the pharmacokinetics of inebilizumab?
A: CD20 B-cells were significantly depleted 1 week after the first infusion, and were below the lower limit of normal (LLN) in all patients 4 weeks from the infusion. They remained under the LLN in 94% of the patients for 28 weeks following the first infusion. T-cell counts remained unchanged, however natural killer cells were transiently decreased in the 2 weeks after the first infusion. Early repletion of B-cells was due to the emergence of transitional and naïve B-cells. While some patients may be early-repleters of their B-cells, in this trial there did not appear to be a relationship between B-cell depletion and relapses. However, in a patient with breakthrough disease, it is recommended that CD19 levels are checked. The mean half-life was 18.0 days. The pharmacokinetics in renal or hepatic impairment have not been studied.
Q: What are the major adverse effects of inebilizumab?
A: Infusion reactions: In the randomized and open label portions of the clinical trial, 12% of patients experienced an infusion-related reaction. These reactions were all mild or moderate and may include symptoms such as headache, nausea, somnolence, dyspnea, fever, myalgias, and rash. Infusion reactions were most common with the first infusion, but can happen with subsequent infusions. For life-threatening infusion reactions, the infusion should be immediately stopped and appropriate supportive treatment should be administered. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.
Infections: The most common infections reported by inebilizumab-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%), which similar to what has been observed with other B-cell depleting therapies. While patients with chronic hepatitis B infection were excluded from the clinical trial, hepatitis B reactivation has been described with other B-cell depleting agents. Additionally, cases of progressive multifocal leukoencephalopathy (PML) and reactivation of latent tuberculosis have been reported with other B-cell depleting agents.
Reduction in serum immunoglobulin levels: Patients taking inebilizumab may experience hypogammaglobulinemia, especially in IgG and IgM levels. At the end of the randomized controlled trial period, immunoglobulin levels decreased by approximately 8% from baseline in inebilizumab-treated participants (~4% decreased in IgG and 32% in IgM). When combined with the open label period, inebilizumab treated patients had a decrease in IgG of 13% and 42% of IgM at 2 years, though it is not clear if this was associated with an increased risk of infection. Mild neutropenia was observed in 6.9% of inebilizumab-treated participants, while moderate neutropenia was seen in 1.9% of inebilizumab-treated participants. At the end of the randomized control period, 12% and 5.3% of inebilizumab treated participants had a neutrophil and lymphocyte count below the LLN respectively. Immunoglobulin levels should be monitored in patients, especially in those with recurrent infections. Consider discontinuing inebilizumab in patients with prolonged hypogammaglobulinemia who develop serious or recurrent infections.
Table: Frequent Adverse Effects Observed in Inebilizumab Clinical Trial
| AQP4 positive group (n=213) |
||
| Inebilizumab | Placebo | |
| Any adverse event | 73% | 71% |
| Any serious adverse event | 4% | 10% |
| Urinary tract infection | 11% | 10% |
| Arthralgia | 10% | 4% |
| Infusion-related reaction | 9% | 10% |
| Back pain | 7% | 4% |
| Headache | 8% | 8% |
| Nasopharyngitis | 7% | 12% |
| Diarrhea | 4% | 6% |
| Upper respiratory tract infection | 3% | 6% |
| Depression | 2% | 10% |
| Oral herpes | 1% | 6% |
| Pain in extremity | 1% | 8% |
| Pruritis | 1% | 10% |
| Vomiting | 1% | 8% |
Q: What pre-testing and monitoring are recommended for patients starting inebilizumab?
A: Prior to starting inebilizumab, all patients must be screened for current or latent hepatitis B infections with a remote hepatitis panel, as well as active or latent tuberculosis infections. Inebilizumab is contraindicated in patients with active hepatitis B infections. A hepatology or infectious disease specialist should be consulted if these screening tests are abnormal. Patients should also be checked for varicella zoster immunity, and vaccinated appropriately if not immune. Additionally, serum immunoglobulins must be checked prior to starting inebilizumab. If these levels are low (IgG <500), an immunologist should be consulted for further guidance. Patients should be monitored for infection while on inebilizumab, and the infusion should be delayed if there is an active infection identified at the time of the infusion until the infection has resolved. Finally, while most patients on B-cell therapy do not require routine monitoring of CD19 counts, these should be checked in the setting of a relapse while on therapy.
Q: Can vaccines be given while on inebilizumab?
A: Any necessary vaccines should be given at least 4 weeks prior to starting inebilizumab. It is not recommended that any live or live-attenuated vaccines be given while on inebilizumab or before B-cell repletion. The recent VELOCE study showed that patients treated with ocrelizumab had an attenuated humoral response to clinically relevant vaccines. The NMO-mentum trial measured levels of tetanus toxoid IgG after the vaccine was given while on inebilizumab, and found no reduction in levels after 197 days. Non-live vaccines should still be given to patients treated with B-cell depleting therapies because the attenuated response is likely still protective. While the ideal timing of vaccination while on therapy is at the end of an infusion cycle, vaccination or infusion should not be delayed for more than a month. This includes the COVID-19 vaccine, which should be given as soon as it is available to the patient.
Q: Pregnancy and inebilizumab
A: Animal studies show that inebilizumab crosses the placenta and depletes B-cells in the fetus. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other B-cell depleting antibodies during pregnancy, which may lead to reduced antibody response in the child. Women of child-bearing potential should be on effective contraception during treatment with inebilizumab, and for 6 months after their last dose. There is no data regarding the risk of breast-feeding while on inebilizumab
In infants of mothers exposed to inebilizumab during pregnancy, live or live-attenuated vaccines should not be administered before confirming recovery of B-cell counts in the infant. Non-live vaccines 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.
Q: How does inebilizumab compare to other therapies used in NMOSD?
A: There are currently 3 FDA-approved medication for adults with AQP4 IgG positive NMOSD (inebilizumab, satralizumab, eculizumab), along with other medications that have been used previously as the mainstay of treatment including rituximab, azathioprine, and mycophenolate mofetil. There have been no head-to-head studies to compare the safety and efficacy of these medications in NMOSD. The decision on which medication to begin with is ultimately up to the treating neurologist and patient and incudes considerations such as route of administration, side effect profile, and cost. The frequency of administration, efficacy and ease of initiating inebilizumab makes it an attractive option as a first-line treatment.
Last Updated: 14 January 2021
References:
- Cree BAC, Bennett JL, Kim HJ, et al. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet 2019; 394: 1352-63.
- Frampton JE. Inebilizumab: First Approval. Drugs 2020; 80: 1259-64.
- Chen D, Gallagher S, Monson NL, Herbst R, Wang Y. Inebilizumab, a B Cell-Depleting Anti-CD19 Antibody for the Treatment of Autoimmune Neurological Diseases: Insights from Preclinical Studies. J Clin Med 2016; 5.
- Yamamura T, Kleiter I, Fujihara K, et al. Trial of Satralizumab in Neuromyelitis Optica Spectrum Disorder. N Engl J Med 2019; 381: 2114-24.
- Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. N Engl J Med 2019; 381: 614-25.
- Tahara M, Oeda T, Okada K, et al. Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2020; 19: 298-306.
- Bar-Or A, Calkwood JC, Chognot C, et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study. Neurology 2020; 95: e1999-e2008.
