Ublituximab is a chimeric monoclonal antibody that selectively targets CD20-expressing cells.
CD20 is a cell surface antigen found on pre-B cells, mature and memory B cells but not expressed on lymphoid stem cells and plasma cells. The binding of ublituximab to CD20 induces lysis of CD20+ B cells primarily through antibody-dependent cell-mediated cytotoxicity (ADCC) and, to a lesser extent through complement-dependent cytotoxicity (CDC). Due to a specific glycosylation pattern of its Fc region, ublituximab displays an increased affinity for the FcγRIIIa (CD16) and antibody-dependent cellular cytolysis against B cells.
Treatment with ublituximab leads to rapid depletion of CD19+ cells in blood by the first day post treatment as an expected pharmacologic effect. This was sustained throughout the treatment period. For the B cell counts, CD19 is used, as the presence of ublituximab interferes with the recognition of CD20 by the assay.
In the Phase III studies, treatment with ublituximab resulted in a median reduction of 97% of CD19+ B cell counts from baseline values after the first infusion in both studies and remained depleted at this level for the duration of dosing.
In the Phase III studies, between each dose of ublituximab, 5.5% of patients showed B-cell repletion (> lower limit of normal (LLN) or baseline) at least at one time point.
The longest follow up time after the last ublituximab infusion in the Phase III studies indicates that the median time to B-cell repletion (return to baseline/LLN whichever occurred first) was 70 weeks.
In the RMS studies, the pharmacokinetics (PK) of ublituximab following repeated intravenous infusions was described by a two-compartment model with first-order elimination and with PK parameters typical for an IgG1 monoclonal antibody. Ublituximab exposures increased in a dose-proportional manner (i.e., linear pharmacokinetics) over the dose range of 150 to 450 mg in patients with RMS. Administration of 150 mg ublituximab by intravenous infusion on Day 1 followed by 450 mg ublituximab by intravenous infusion over one hour on Day 15, Week 24 and Week 48 led to a geometric mean steady-state AUC of 3000 μg/mL per day (CV=28%) and a mean maximum concentration of 139 μg/mL (CV=15%).
Ublituximab is administered as an intravenous infusion. There have been no studies performed with other routes of administration.
In the population pharmacokinetic analysis of ublituximab, the central volume of distribution was estimated to be 3.18 L and the peripheral volume of distribution was estimated to be 3.6 L.
The metabolism of ublituximab has not been directly studied, as antibodies are cleared principally by catabolism (i.e. breakdown into peptides and amino acids).
Following intravenous infusion of 150 mg ublituximab on Day 1 followed by 450 mg ublituximab on Day 15, Week 24 and Week 48, the mean terminal elimination half-life of ublituximab was estimated to be 22 days.
No studies have been conducted to investigate the pharmacokinetics of ublituximab in children and adolescents <18 years of age.
There are no dedicated PK studies of ublituximab in patients ≥ 55 years due to limited clinical experience.
No specific studies of ublituximab in patients with renal impairment have been performed. Patients with mild renal impairment were included in the clinical studies. There is no experience in patients with moderate and severe renal impairment. However, as ublituximab is not excreted via urine, it is not expected that patients with renal impairment require dose modification.
No specific studies of ublituximab in patients with hepatic impairment have been performed.
Since hepatic metabolism of monoclonal antibodies such as ublituximab is negligible, hepatic impairment is not expected to impact its pharmacokinetics. Therefore, it is not expected that patients with hepatic impairment require dose modification.
Non-clinical data reveal no special hazard for humans based on repeated dose toxicity studies and in vitro mutagenicity studies. Carcinogenicity studies have not been conducted with ublituximab.
In an enhanced pre- and post-natal development study, pregnant cynomolgus monkeys were administered weekly intravenous doses of 30 mg/kg ublituximab (corresponding to AUC 26 times the AUC in patients at the maximum recommended dose) during either the first, second or third trimester of pregnancy, which resulted in maternal moribundity and foetal loss. Pathological observations in exposed dams involved multiple organ systems (thrombi in multiple organs, vascular necrosis in the intestine and liver, inflammation and oedema in the lungs and heart) as well as the placenta and these findings were consistent with immune-mediated adverse effects secondary to immunogenicity.
Infant abnormalities were absent in dams exposed during the first trimester of pregnancy. Ublituximab-related external, visceral and skeletal abnormalities were noted in two infants from dams treated during the second trimester of pregnancy. Histopathology evaluations revealed minimal to moderate degeneration/necrosis in the brain. Foetal findings included contractures and abnormal flexion of multiple limbs and tail, shortened mandible, elongate calvarium, enlargement of ears, and/or craniomandibular abnormalities which were attributed to brain necrosis. These findings were potentially related to the immunogenic response of ublituximab in the mothers, which affected the placental exchange of nutrients.
The presence of ublituximab in mother’s milk was not assessed.
© 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.
