Ocrelizumab is a recombinant humanised monoclonal antibody that selectively targets CD20-expressing B 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 precise mechanisms through which ocrelizumab exerts its therapeutic clinical effects in MS is not fully elucidated but is presumed to involve immunomodulation through the reduction in the number and function of CD20-expressing B cells. Following cell surface binding, ocrelizumab selectively depletes CD20-expressing B cells through antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. The capacity of B-cell reconstitution and preexisting humoral immunity are preserved. In addition, innate immunity and total T-cell numbers are not affected.
Treatment with ocrelizumab leads to rapid depletion of CD19+ B cells in blood by 14 days post treatment (first time-point of assessment) as an expected pharmacologic effect. This was sustained throughout the treatment period. For the B-cell counts, CD19 is used, as the presence of ocrelizumab interferes with the recognition of CD20 by the assay.
In the Phase III adult studies, between each dose of ocrelizumab, up to 5% of patients showed B-cell repletion (>LLN or baseline) at least at one time point. The extent and duration of B-cell depletion was consistent in the PPMS and RMS trials.
The longest follow up time after the last infusion (Phase II study WA21493, N=51) indicates that the median time to B-cell repletion (return to baseline/LLN whichever occurred first) was 72 weeks (range 27–175 weeks). 90% of all patients had their B-cells repleted to LLN or baseline by approximately two and a half years after the last infusion.
The pharmacokinetics of ocrelizumab in the MS studies were described by a two compartment model with time-dependent clearance, and with PK parameters typical for an IgG1 monoclonal antibody.
The overall exposure (AUC over the 24 weeks dosing interval) was identical in the 2 x 300 mg in PPMS and 1 x 600 mg in RMS studies, as expected given an identical dose was administered. Area under the curve (AUCτ) after the 4th dose of 600 mg ocrelizumab was 3510 μg/mL•day, and mean maximum concentration (Cmax) was 212 μg/mL in RMS (600 mg infusion) and 141 μg/mL in PPMS (300 mg infusions).
After administration of 920 mg subcutaneous ocrelizumab, the predicted mean exposure (AUC over the 24 week dosing interval) was 3730 μg/mL•day. The primary PK endpoint in OCARINA II, AUCw1-12, after 920 mg subcutaneous ocrelizumab was shown to be non-inferior to 600 mg intravenous ocrelizumab. The geometric mean ratio for AUCw1-12 was 1.29 (90% CI: 1.23–1.35).
Ocrelizumab is administered as an intravenous infusion.
The estimated bioavailability after subcutaneous administration of 920 mg ocrelizumab was 81%. The mean Cmax was 132 μg/mL and tmax was reached after approximately 4 days (range 2-13 days).
The population pharmacokinetics estimate of the central volume of distribution was 2.78 L. Peripheral volume and inter-compartment clearance were estimated at 2.68 L and 0.294 L/day.
The metabolism of ocrelizumab has not been directly studied, as antibodies are cleared principally by catabolism (i.e. breakdown into peptides and amino acids).
Constant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at 0.0489 L/day which declined with a half-life of 33 weeks. The terminal elimination half-life of ocrelizumab was 26 days.
The median AUC over the first 24-week dosing interval was 3130 μg/mL•day, and Cmax was 147 μg/mL, in paediatric patients aged 10 years and older with RRMS receiving ocrelizumab 600 mg (body weight 35 kg or more) or 300 mg (body weight less than 35 kg).
The recommended posology is derived from the PK model, which was based on clinical data from 110 patients with a body weight of 40 kg or higher receiving 600 mg ocrelizumab, and 6 patients from the Phase II study weighing less than 40 kg receiving 300 mg ocrelizumab.
No studies have been conducted to investigate the pharmacokinetics of ocrelizumab in paediatric patients less than 10 years of age.
No studies have been conducted to investigate the pharmacokinetics of subcutaneous ocrelizumab in children and adolescents less than 18 years of age.
There are no dedicated PK studies of ocrelizumab in patients ≥55 years due to limited clinical experience.
No formal pharmacokinetic study has been conducted. Patients with mild renal impairment were included in clinical trials and no change in the pharmacokinetics of ocrelizumab was observed in those patients. There is no PK information available in patients with moderate or severe renal impairment.
No formal pharmacokinetic study has been conducted. Patients with mild hepatic impairment were included in clinical trials, and no change in the pharmacokinetics was observed in those patients. There is no PK information available in patients with moderate or severe hepatic impairment.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and embryo-foetal development. Neither carcinogenicity nor mutagenicity studies have been conducted with ocrelizumab.
In two pre- and post-natal development studies in cynomolgus monkeys, administration of ocrelizumab from gestation day 20 to at least parturition was associated with glomerulopathy, lymphoid follicle formation in bone marrow, lymphoplasmacytic renal inflammation, and decreased testicular weight in offspring. The maternal doses administered in these studies resulted in maximum mean serum concentrations (Cmax) that were 4.5- to 21-fold above those anticipated in the clinical setting.
There were five cases of neonatal moribundities, one attributed to weakness due to premature birth accompanied by opportunistic bacterial infection, one due to an infective meningoencephalitis involving the cerebellum of the neonate from a maternal dam with an active bacterial infection (mastitis) and three with evidence of jaundice and hepatic damage, with a viral aetiology suspected, possibly a polyomavirus. The course of these five confirmed or suspected infections could have potentially been impacted by B-cell depletion. Newborn offspring of maternal animals exposed to ocrelizumab were noted to have depleted B cell populations during the post-natal phase.
© 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.