Mepolizumab is an IL-5 antagonist (IgG1 kappa) that binds to IL-5, inhibiting its bioactivity with nanomolar potency by blocking its binding to the IL-5R alpha complex on the cell surface. IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation and survival of eosinophils. In patients where their disease is driven by type 2 inflammation, IL-5 is an important component of the processes driving the pathogenesis of asthma, CRSwNP, COPD, EGPA and HES. Additional structural and inflammatory cell types also express the IL-5R alpha e.g., epithelial cells, mast cells, plasma cells, basophils, ILC-2 cells, T cells, smooth muscle cells, neutrophils and fibroblasts. In severe asthma and CRSwNP, inhibition of IL-5 has been associated with an improvement in aspects of airway remodelling. However, the mechanism of action in these cells and across the different diseases has not been definitively established.
In patients with severe refractory eosinophilic asthma (adults/adolescents), following a dose of 100 mg administered subcutaneously every 4 weeks for 32 weeks, blood eosinophils were reduced from a geometric mean count at baseline of 290 to 40 cells/μL at week 32 (n=182), a reduction of 84% compared to placebo.
This magnitude of blood eosinophils reduction was maintained in severe refractory eosinophilic asthma patients (n=998) treated for a median of 2.8 years (range 4 weeks to 4.5 years) in open-label extension studies.
In children aged 6 to 11 years old with severe refractory eosinophilic asthma administered mepolizumab subcutaneously every 4 weeks for 52 weeks, blood eosinophils were reduced from a geometric mean count at baseline to week 52 of 306 (n=16) to 48 (n=15) following 40 mg (for a weight <40kg) and 331 to 44 cells/μL (n=10) following 100 mg (for a weight ≥40 kg), a reduction from baseline of 85% and 87%, respectively.
In adults, adolescents and children, this magnitude of reduction was observed within 4 weeks of treatment.
In patients with CRSwNP, following a 100 mg dose of mepolizumab administered subcutaneously every 4 weeks for 52 weeks, blood eosinophils were reduced from a geometric mean count at baseline to week 52 of 390 (n=206) to 60 cells/μL (n=126), which corresponds to a geometric mean reduction of 83% compared to placebo. This magnitude of reduction was observed within 4 weeks of treatment and was maintained throughout the treatment period of 52 weeks.
In patients with COPD, following a 100 mg dose of mepolizumab administered subcutaneously every 4 weeks for 52 (and up to 104) weeks, blood eosinophils were reduced from a geometric mean count at baseline of 480 (n=403) to 60 cells/μL at week 52 (n=257) and week 104 (n=61), which corresponds to a geometric mean reduction of 79% at week 52 and 80% at week 104 compared to placebo. This magnitude of reduction was observed within 4 weeks of treatment.
In patients with EGPA, following a 300 mg dose of mepolizumab administered subcutaneously every 4 weeks for 52 weeks, blood eosinophils were reduced from a geometric mean count at baseline of 177 (n=68) to 38 cells/μL (n=64) at week 52. There was a geometric mean reduction of 83% compared to placebo and this magnitude of reduction was observed within 4 weeks of treatment.
In patients with HES (adults/adolescents), following a 300 mg dose of mepolizumab administered subcutaneously every 4 weeks for 32 weeks, blood eosinophil reduction was observed within 2 weeks of treatment. At week 32, blood eosinophils were reduced from a geometric mean count at baseline of 1 460 (n=54) to 70 cells/μL (n=48) and a geometric mean reduction of 92% compared to placebo was observed. This magnitude of reduction was maintained for a further 20 weeks in patients that continued mepolizumab treatment in the open-label extension study.
Following subcutaneous dosing in patients with asthma and CRSwNP, mepolizumab exhibited approximately dose-proportional pharmacokinetics over a dose range of 12.5 mg to 250 mg. Subcutaneous administration of mepolizumab 300 mg had approximately three times the systemic exposure of mepolizumab 100 mg. Mepolizumab pharmacokinetics were consistent in patients with asthma, CRSwNP, COPD, EGPA or HES. Following administration of a single 100 mg subcutaneous dose in healthy subjects, mepolizumab systemic exposure was comparable between formulations.
Following subcutaneous administration to healthy subjects or patients with asthma, mepolizumab was absorbed slowly with a median time to reach maximum plasma concentration (Tmax) ranging from 4 to 8 days.
Following a single subcutaneous administration in the abdomen, thigh or arm of healthy subjects, mepolizumab absolute bioavailability was 64%, 71% and 75%, respectively. In patients with asthma the absolute bioavailability of mepolizumab administered subcutaneously in the arm ranged from 74- 80%. Following repeat subcutaneous administration every 4 weeks, there is approximately a two-fold accumulation at steady state.
Following a single intravenous administration to patients with asthma, mepolizumab distributes into a mean volume of distribution of 55 to 85 mL/kg.
Mepolizumab is a humanised IgG1 monoclonal antibody degraded by proteolytic enzymes which are widely distributed in the body and not restricted to hepatic tissue.
Following a single intravenous administration to patients with asthma, the mean systemic clearance (CL) ranged from 1.9 to 3.3 mL/day/kg, with a mean terminal half-life of approximately 20 days. Following subcutaneous administration of mepolizumab the mean terminal half-life (t½) ranged from 16 to 22 days. In the population pharmacokinetic analysis estimated mepolizumab systemic clearance was 3.1 mL/day/kg.
There are limited pharmacokinetic data available in elderly patients (≥65 years old) across all clinical studies (N=90). However, in the population pharmacokinetic analysis, there were no indications of an effect of age on the pharmacokinetics of mepolizumab over the age range of 12 to 82 years.
No formal studies have been conducted to investigate the effect of renal impairment on the pharmacokinetics of mepolizumab. Based on population pharmacokinetic analyses, no dose adjustment is required in patients with creatinine clearance values between 50-80 mL/min. There are limited data available in patients with creatinine clearance values <50 mL/min.
No formal studies have been conducted to investigate the effect of hepatic impairment on the pharmacokinetics of mepolizumab. Since mepolizumab is degraded by widely distributed proteolytic enzymes, not restricted to hepatic tissue, changes in hepatic function are unlikely to have any effect on the elimination of mepolizumab.
Severe eosinophilic asthma and HES:
There are limited pharmacokinetic data available in the paediatric population (59 patients with eosinophilic esophagitis, 55 patients with severe refractory eosinophilic asthma and 1 patient with HES). Intravenous mepolizumab pharmacokinetics was evaluated by population pharmacokinetic analysis in a paediatric study conducted in patients aged 2–17 years old with eosinophilic esophagitis.
Paediatric pharmacokinetics was largely predictable from adults, after taking into account bodyweight. Mepolizumab pharmacokinetics in adolescent patients with severe refractory eosinophilic asthma or HES included in the phase 3 studies were consistent with adults.
Paediatric pharmacokinetics following subcutaneous administration in patients 6 to 11 years old with severe refractory eosinophilic asthma was investigated in an open label, uncontrolled study of 12-weeks duration. Paediatric pharmacokinetics were broadly consistent with adults and adolescents after accounting for bodyweight and bioavailability. The absolute subcutaneous bioavailability appears complete compared to that observed in adults and adolescents of 76%. Exposure following subcutaneous administration of either 40 mg (for a weight <40 kg) or 100 mg (for a weight ≥40 kg) was 1.32 and 1.97 times of that observed in adults at 100 mg.
Investigation of a 40 mg subcutaneous dosing regimen administered every 4 weeks in children 6 to 11 years old over a 15-70 kg broad weight range by PK modelling and simulation predicts that the exposure of this dosing regimen would remain on average within 38% of adults at 100 mg. This dosing regimen is considered acceptable due to the wide therapeutic index of mepolizumab.
EGPA:
Mepolizumab pharmacokinetics in children (6 to 17 years old) with EGPA were predicted using modelling and simulation, based on pharmacokinetics in other eosinophilic diseases, and are expected to be consistent with those observed in children with severe eosinophilic asthma. The recommended posology in children 6 to 11 years old over a 15-70 kg broad weight range predicts that the exposure would remain on average within 26% of adults at 300 mg.
As mepolizumab is a monoclonal antibody, no genotoxicity or carcinogenicity studies have been conducted.
Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology or repeated dose toxicity studies in monkeys. Intravenous and subcutaneous administration to monkeys was associated with reductions in peripheral and lung eosinophil counts, with no toxicological findings.
Eosinophils are thought to be associated with immune system responses to some parasitic infections. Studies conducted in mice treated with anti-IL-5 antibodies or genetically deficient in IL-5 or eosinophils have not shown impaired ability to clear parasitic infections. The relevance of these findings for humans is unknown.
No impairment of fertility was observed in a fertility and general reproduction toxicity study in mice performed with an analogous antibody that inhibits IL-5 in mice. This study did not include a littering or functional offspring assessment.
In monkeys, mepolizumab had no effect on pregnancy or on embryonic/fetal and postnatal development (including immune function) of the offspring. Examinations for internal or skeletal malformations were not performed. Data in cynomolgus monkeys demonstrate that mepolizumab crossed the placenta. Concentrations of mepolizumab were about 1.2-2.4 times higher in infants than in mothers for several months post partum and did not affect the immune system of the infants.
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