Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: GlaxoSmithKline Trading Services Limited, Currabinny, Carrigaline, County Cork, Ireland
Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airway diseases
ATC code: R03DX09
Mepolizumab is a humanised monoclonal antibody (IgG1, kappa), which targets human interleukin-5 (IL-5) with high affinity and specificity. IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation and survival of eosinophils. Mepolizumab inhibits the bioactivity of IL-5 with nanomolar potency by blocking the binding of IL-5 to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface, thereby inhibiting IL-5 signalling and reducing the production and survival of eosinophils.
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.
Consistent with the potentially immunogenic properties of protein and peptide therapeutics, patients may develop antibodies to mepolizumab following treatment. In the placebo-controlled trials, 15/260 (6%) of adults and adolescents treated with 100 mg dose subcutaneously had detectable anti-mepolizumab antibodies after having received at least one dose of mepolizumab.
The immunogenicity profile of mepolizumab 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 was similar to that observed in the placebo-controlled studies.
In children aged 6 to 11 years old with severe refractory eosinophilic asthma following either 40 mg subcutaneously (for a weight <40kg) or 100 mg subcutaneously (for a weight ≥40 kg), 2/35 (6%) had detectable anti-mepolizumab antibodies after having received at least one dose of mepolizumab during the initial short phase of the study. No children had detectable anti-mepolizumab antibodies during the long-term phase of the study. Neutralising antibodies were detected in one adult subject. Anti-mepolizumab antibodies did not discernibly impact the pharmacokinetics and pharmacodynamics of mepolizumab in the majority of patients and there was no evidence of a correlation between antibody titres and change in blood eosinophil level.
The efficacy of mepolizumab in the treatment of a targeted group of patients with severe refractory eosinophilic asthma was evaluated in 3 randomised, double-blind, parallel-group clinical studies of between 24-52 weeks duration, in patients aged 12 years and older. These patients either remained uncontrolled (at least two severe exacerbations in the previous 12 months) on their current standard of care, including at least high doses of inhaled corticosteroids (ICS) plus an additional maintenance treatment(s), or were dependent on systemic corticosteroids. Additional maintenance treatments included long-acting beta2-adrenergic agonists (LABA), leukotriene modifiers, long-acting muscarinic antagonists (LAMA), theophylline, and oral corticosteroids (OCS).
The two exacerbations studies MEA112997 and MEA115588 enrolled a total of 1192 patients, 60% females, with a mean age of 49 years (range 12–82). The proportion of patients on maintenance OCS was 31% and 24%, respectively. Patients were required to have a history of two or more severe asthma exacerbations requiring oral or systemic corticosteroid treatment in the past 12 months and reduced lung function at baseline (pre-bronchodilator FEV1 <80% in adults and <90% in adolescents). The mean number of exacerbations in the previous year was 3.6 and the mean predicted pre-bronchodilator FEV1 was 60%. Patients continued to receive their existing asthma medicine during the studies.
For the oral corticosteroid-sparing study MEA115575, a total of 135 patients were enrolled (55% were female; mean age of 50 years) who were being treated daily with OCS (5-35 mg per day), and high-dose ICS plus an additional maintenance medicine.
In MEA112997, a randomised, double-blind, placebo-controlled, parallel-group, multi-centre study of 52 weeks duration in 616 patients with severe refractory eosinophilic asthma, mepolizumab significantly reduced clinically significant asthma exacerbations (defined as worsening of asthma requiring use of oral/systemic corticosteroids and/or hospitalisation and/or emergency department visits) when administered in doses of 75 mg, 250 mg or 750 mg intravenously compared to placebo (see Table 1).
Table 1. Frequency of clinically significant exacerbations at week 52 in the intent to treat population:
| Intravenous Mepolizumab | Placebo | |||
|---|---|---|---|---|
| 75 mg n=153 | 250 mg n=152 | 750 mg n=156 | n=155 | |
| Exacerbation rate/year | 1,24 | 1,46 | 1,15 | 2,40 |
| Percent reduction | 48% | 39% | 52% | |
| Rate ratio (95% CI) | 0,52 (0,39, 0,69) | 0,61(0,46, 0,81) | 0,48 (0,36, 0,64) | |
| p-value | <0,001 | <0,001 | <0,001 | - |
MEA115588 was a randomised, double-blind, placebo-controlled, parallel-group, multi-centre study which evaluated the efficacy and safety of mepolizumab as add-on therapy in 576 patients with severe refractory eosinophilic asthma defined as peripheral blood eosinophils greater than or equal to 150 cells/μL at initiation of treatment or greater than or equal to 300 cells/μL within the past 12 months.
Patients received mepolizumab 100 mg administered subcutaneously, mepolizumab 75 mg administered intravenously or placebo treatment once every 4 weeks over 32 weeks. The primary endpoint was the frequency of clinically significant exacerbations of asthma and the reductions for both mepolizumab treatment arms compared to placebo were statistically significant (p<0.001). Table 2 provides the results of the primary and secondary endpoints for patients treated with subcutaneous mepolizumab or placebo.
Table 2. Results of primary and secondary endpoints at week 32 in the intent to treat population (MEA115588):
| Mepolizumab 100 mg (subcutaneous) N=194 | Placebo N=191 | |
|---|---|---|
| Primary endpoint | ||
| Frequency of clinically significant exacerbations | ||
| Exacerbation rate per year | 0,83 | 1,74 |
| Percent reduction | 53% | - |
| Rate ratio (95% CI) | 0,47 (0,35, 0,64) | |
| p-value | <0,001 | |
| Secondary endpoints | ||
| Frequency of exacerbations requiring hospitalisations/emergency room visits | ||
| Exacerbation rate per year | 0,08 | 0,20 |
| Percent reduction | 61% | - |
| Rate ratio (95% CI) | 0,39 (0,18, 0,83) | |
| p-value | 0,015 | |
| Frequency of exacerbations requiring hospitalisation | ||
| Exacerbations rate per year | 0,03 | 0,10 |
| Percent reduction | 69% | - |
| Rate ratio (95% CI) | 0,31 (0,11, 0,91) | |
| p-value | 0,034 | |
| Pre-bronchodilator FEV1 (mL) at week 32 | ||
| Baseline (SD) | 1730 (659) | 1860 (631) |
| Mean Change from Baseline (SE) | 183 (31) | 86 (31) |
| Difference (mepolizumab vs. placebo) | 98 | |
| 95% CI | (11, 184) | |
| p-value | 0,028 | |
| St. George’s Respiratory Questionnaire (SGRQ) at week 32 | ||
| Baseline (SD) | 47,9 (19,5) | 46,9 (19,8) |
| Mean Change From Baseline (SE) | -16,0 (1,1) | -9,0 (1,2) |
| Difference (mepolizumab vs. placebo) | -7,0 | |
| 95% CI | (-10,2, -3,8) | |
| p-value | <0,001 | |
Table 3 shows the results of a combined analysis of the two exacerbation studies (MEA112997 and MEA115588) by baseline blood eosinophil count. The rate of exacerbations in the placebo arm increased with increasing baseline blood eosinophil count. The reduction rate with mepolizumab was greater in patients with higher blood eosinophil counts.
Table 3. Combined analysis of the rate of clinically significant exacerbations by baseline blood eosinophil count in patients with severe refractory eosinophilic asthma:
| Mepolizumab 75 mg IV/100 mg SC N=538 | Placebo N=346 | |
|---|---|---|
| MEA112997+MEA115588 | ||
| <150 cells/μL | ||
| n | 123 | 66 |
| Exacerbation rate per year | 1,16 | 1,73 |
| Mepolizumab vs. placebo | ||
| Rate ratio (95% CI) | 0,67 (0,46, 0,98) | --- |
| 150 to <300 cells/μL | ||
| n | 139 | 86 |
| Exacerbation rate per year | 1,01 | 1,41 |
| Mepolizumab vs. placebo | ||
| Rate ratio (95% CI) | 0,72 (0,47, 1,10) | --- |
| 300 to <500 cells/μL | ||
| n | 109 | 76 |
| Exacerbation rate per year | 1,02 | 1,64 |
| Mepolizumab vs. placebo | ||
| Rate ratio (95% CI) | 0,62 (0,41, 0,93) | --- |
| ≥500 cells/μL | ||
| N | 162 | 116 |
| Exacerbation rate per year | 0,67 | 2,49 |
| Mepolizumab vs. placebo | ||
| Rate ratio (95% CI) | 0,27 (0,19, 0,37) | --- |
MEA115575 evaluated the effect of mepolizumab 100 mg administered subcutaneously on reducing the requirement for maintenance oral corticosteroids (OCS) while maintaining asthma control in subjects with severe refractory eosinophilic asthma. Patients had a blood eosinophil count of ≥150/μL at baseline or a blood eosinophil count of ≥300/μL in the 12 months prior to screening. Patients were administered mepolizumab or placebo treatment once every 4 weeks over the treatment period. Patients continued to receive their existing asthma medicine during the study with the exception of their OCS dose which was reduced every 4 weeks during the OCS reduction phase (Weeks 4-20), as long as asthma control was maintained.
A total of 135 patients were enrolled: mean age was 50 years, 55% were female, and 48% had been receiving oral steroid therapy for at least 5 years. The baseline mean prednisone equivalent dose was approximately 13 mg per day.
The primary endpoint was the percent reduction in daily OCS dose (weeks 20-24), whilst maintaining asthma control by defined dose reduction categories (see Table 4). Predefined categories included percent reductions ranging from 90-100% reduction, to no decrease in the prednisone dose from the end of the optimisation phase. The comparison between mepolizumab and placebo was statistically significant (p=0.008).
Table 4. Results of the primary and secondary endpoints in MEA115575:
| ITT Population | ||
|---|---|---|
| Mepolizumab 100 mg (subcutaneous) N=69 | Placebo N=66 | |
| Primary endpoint | ||
| Percent reduction in OCS from baseline (weeks 20-24) | ||
| 90% - 100% | 16 (23%) | 7 (11%) |
| 75% - <90% | 12 (17%) | 5 (8%) |
| 50% - <75% | 9 (13%) | 10 (15%) |
| >0% - <50% | 7 (10%) | 7 (11%) |
| No decrease in OCS/lack of asthma control/withdrawal from treatment | 25 (36%) | 37 (56%) |
| Odds ratio (95% CI) | 2,39 (1,25, 4,56) | |
| p-value | 0,008 | |
| Secondary endpoints (weeks 20-24) | ||
| Reduction in the daily OCS dose to 0 mg/d | 10 (14%) | 5 (8%) |
| Odds ratio (95% CI) | 1,67 (0,49, 5,75) | |
| p-value | 0, 414 | |
| Reduction in the daily OCS dose to ≤5mg/day | 37 (54%) | 21 (32%) |
| Odds ratio (95% CI) | 2,45 (1,12, 5,37) | |
| p-value | 0,025 | |
| Median % reduction in daily OCS dose from baseline (95% CI) | 50,0 (20,0, 75,0) | 0,0 (-20,0, 33,3) |
| Median difference (95% CI ) | -30,0 (-66,7, 0,0) | |
| p-value | 0,007 | |
Open-label extension studies in severe refractory eosinophilic asthma MEA115666 (COLUMBA), MEA115661 (COSMOS) and 201312 (COSMEX)
The long-term efficacy profile of Nucala 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 MEA115666, MEA115661 and 201312 was generally consistent with the 3 placebo-controlled studies.
In MEA115588 and in the double-blind placebo-controlled study 200862, there were 34 adolescents (12 to 17 years old). Of these 34 subjects: 12 received placebo, 9 received mepolizumab 75 mg intravenously, and 13 received 100 mg subcutaneously. In a combined analysis of these studies, a 40% reduction in clinically significant exacerbations was observed in adolescents following mepolizumab treatment compared to placebo (rate ratio 0.60; 95% CI: 0.17, 2.10).
Following subcutaneous dosing in patients with asthma, mepolizumab exhibited approximately dose-proportional pharmacokinetics over a dose range of 12.5 mg to 250 mg.
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 humanized 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 (t1/2) 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 the paediatric population (59 subjects with eosinophilic esophagitis, 55 subjects with severe refractory eosinophilic asthma). Intravenous mepolizumab pharmacokinetics was evaluated by population pharmacokinetic analysis in a paediatric study conducted in subjects aged 2–17 years old with eosinophilic esophagitis. Paediatric pharmacokinetics was largely predictable from adults, after taking into account bodyweight. Mepolizumab pharmacokinetics in adolescent subjects with severe refractory eosinophilic asthma included in the phase 3 studies were consistent with adults (see section 4.2).
Paediatric pharmacokinetics following subcutaneous administration in subjects 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 <40kg) 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.
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.
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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