Inebilizumab is a monoclonal antibody that specifically binds to CD19, a cell surface antigen present on pre-B and mature B-cell lymphocytes, including plasmablasts and some plasma cells. Following cell surface binding to B lymphocytes, inebilizumab supports antibody-dependent cellular cytolysis (ADCC) and antibody-dependent cellular phagocytosis (ADCP). B cells are believed to play a central role in the pathogenesis of NMOSD. The precise mechanism by which inebilizumab exerts its therapeutic effects in NMOSD is unknown but is presumed to involve B-cell depletion and may include the suppression of antibody secretion, antigen presentation, B cell–T cell interaction, and the production of inflammatory mediators.
Pharmacodynamics of inebilizumab were assessed with an assay for CD20+ B cells, since inebilizumab can interfere with the CD19+ B-cell assay. Treatment with inebilizumab reduces CD20+ B-cell counts in blood by 8 days after infusion. In a clinical study of 174 patients, CD20+ B-cell counts were reduced below the lower limit of normal by 4 weeks in 100% of patients treated with inebilizumab and remained below the lower limit of normal in 94% of patients for 28 weeks after initiation of treatment. The time to B-cell repletion following administration of inebilizumab is not known.
In the pivotal study of NMOSD patients the prevalence of anti-drug antibodies (ADA) was 14.7% at the end of the OLP; the overall incidence of treatment-emergent ADA was 7.1% (16 of 225) and the occurrence and titer of ADA positive timepoints decreased over time with inebilizumab treatment. ADA-positive status appeared to have no clinically relevant impact on PK and PD (B-cell) parameters and did not impact the long-term safety profile. There was no apparent effect of ADA status on the efficacy outcome; however, the impact cannot be fully assessed given the low incidence of ADA associated with inebilizumab treatment.
Inebilizumab is administered as an intravenous infusion.
Based on population pharmacokinetic analysis, the estimated typical central and peripheral volume of distribution of inebilizumab was 2.95 L and 2.57 L, respectively.
Inebilizumab is a humanised IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body.
In adult patients with NMOSD, the terminal elimination half-life was approximately 18 days. From population pharmacokinetic analysis, the estimated inebilizumab systemic clearance of the first-order elimination pathway was 0.19 L/day. At low pharmacokinetic exposure levels, inebilizumab was likely subject to the receptor (CD19)-mediated clearance, which decreased with time presumably due to the depletion of B cells by inebilizumab treatment.
Inebilizumab has not been studied in adolescents or children.
Based on population pharmacokinetic analysis, age did not affect inebilizumab clearance.
A population pharmacokinetic analysis indicated that there was no significant effect of gender and race on inebilizumab clearance.
No formal clinical studies have been conducted to investigate the effect of renal impairment on inebilizumab. Due to the large molecular weight and hydrodynamic size of an IgG monoclonal antibody, inebilizumab is not expected to be filtered through the glomerulus. From population pharmacokinetic analysis, inebilizumab clearance in patients with varying degrees of renal impairment was comparable to patients with normal estimated glomerular filtration rate.
No formal clinical studies have been conducted to investigate the effect of hepatic impairment on inebilizumab. In clinical studies, no subjects with severe hepatic impairment have been exposed to inebilizumab. IgG monoclonal antibodies are not primarily cleared via the hepatic pathway; change in hepatic function is, therefore, not expected to influence inebilizumab clearance. Based on population pharmacokinetic analysis, baseline hepatic function biomarkers (AST, ALP, and bilirubin) had no clinically relevant effect on inebilizumab clearance.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.
Inebilizumab was evaluated in a combined fertility and embryo-foetal development study in female and male huCD19 Tg mice at intravenous doses of 3 and 30 mg/kg. There was no effect on embryo-foetal development, however, there was a treatment-related reduction in fertility index at both tested doses. The relevance of this finding to humans is unknown. Additionally, there was a decrease in B-cell populations at the site of B-cell development in foetal mice born to inebilizumab-treated animals as compared to the offspring of control animals, suggesting that inebilizumab crosses the placenta and depletes B cells.
Only sparse toxicokinetic samples were collected in the combined fertility and embryo-foetal development study; based on first dose maximum concentration (Cmax), the exposure multiples of 3 and 30 mg/kg in female huCD19 Tg mice were 0.4-fold and 4-fold respectively for the 300 mg clinical therapeutic dose.
In a pre-/postnatal development study in transgenic mice, administration of inebilizumab to maternal animals from Gestation Day 6 to Lactation Day 20 resulted in depleted B-cell populations in offspring at postnatal Day 50. B-cell populations in offspring recovered by postnatal Day 357. The immune response to neoantigen in offspring of animals treated with inebilizumab was decreased relative to offspring of control animals, suggestive of impairment of normal B-cell function.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
