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Pharmacology: Pharmacodynamics: Mechanism of action: Mepolizumab is a humanized 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 signaling and reducing the production and survival of eosinophils.
Pharmacodynamic effects: Severe asthma: In clinical trials, reduction in blood eosinophils was observed consistently following treatment with NUCALA. The magnitude and duration of this reduction was dose-dependent. Following a dose of 100 mg administered subcutaneously every 4 weeks for 32 weeks, the blood eosinophils were reduced to a geometric mean count of 40 cells/μL. This corresponds to a geometric mean reduction of 84% compared to placebo. This magnitude of reduction was observed within 4 weeks of treatment. This magnitude of blood eosinophils reduction was maintained in severe asthma patients (n=998) treated for a median of 2.8 years (range 4 weeks to 4.5 years) in open-label extension studies.
Immunogenicity: Severe asthma: Consistent with the potentially immunogenic properties of protein and peptide therapeutics, patients may develop antibodies to mepolizumab following treatment. Overall, 15/260 (6%) of subjects with severe asthma treated with 100 mg dose subcutaneously developed anti-mepolizumab antibodies after having received at least one dose of mepolizumab. The immunogenicity profile of mepolizumab in severe 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.
Neutralizing antibodies were detected in one subject receiving mepolizumab. Anti-mepolizumab antibodies did not discernibly impact the PK or PD of mepolizumab treatment in the majority of patients and there was no evidence of a correlation between antibody tires and change in eosinophil level.
Clinical Studies: Severe asthma: The efficacy of NUCALA in the treatment of a targeted group of subjects with severe eosinophilic asthma was evaluated in 3 randomized, double-blind, parallel-group clinical studies of between 24-52 weeks duration, in patients aged 12 years and older. These studies were designed to evaluate the efficacy of NUCALA administered once every 4 weeks by subcutaneous or intravenous injection in severe eosinophilic asthma patients not controlled on their standard of care [e.g., inhaled corticosteroids (ICS), oral corticosteroids (OCS), combination ICS and long-acting beta2-adrenergic agonists (LABA), leukotriene modifiers, short-acting beta2-adrenergic agonists (SABA)].
Placebo Controlled Studies: Dose-ranging Efficacy MEA112997 (DREAM) Study: In MEA112997, a randomized, double-blind, placebo-controlled, parallel-group, multi-center study of 52 weeks duration in 616 patients, results demonstrated that mepolizumab (75 mg, 250 mg or 750 mg) significantly reduced asthma exacerbations when administered intravenously compared to placebo. There was no statistically significant difference in effect seen between the 3 studied doses. Blood eosinophil counts greater than or equal to 150 cells/μl at screening; or blood eosinophils ≥300 cells/μl in the past 12 months predicted subjects who would benefit most from NUCALA therapy. Results from this study were used to determine dose selection for the studies using subcutaneous mepolizumab administration. NUCALA is not indicated for intravenous use, and should only be administered by the subcutaneous route.
Exacerbation Reduction MEA115588 (MENSA) Study: MEA115588 was a randomized, double-blind, placebo-controlled, parallel-group, multi-center study which evaluated the efficacy and safety of mepolizumab as add-on therapy in 576 patients with severe eosinophilic asthma. This study evaluated the frequency of clinically significant exacerbations of asthma, defined as: worsening of asthma requiring use of oral/systemic corticosteroids and/or hospitalization and/or emergency department visits.
Patients were aged 12 years of age or older, with a history of two or more asthma exacerbations in the past 12 months and not controlled on their current asthma drug therapies [i.e., high-dose inhaled corticosteroids (ICS) in combination with at least another controller such as long-acting beta2-adrenergic agonists (LABA) or leukotriene modifiers]. Patients were allowed to be on oral corticosteroid therapy and continued to receive their existing asthma medication during the study. Severe eosinophilic asthma patients were identified by peripheral blood eosinophils greater than or equal to 150 cells/μl within 6 weeks of randomization (first dose) or blood eosinophils greater than or equal to 300 cells/μl within the past 12 months of randomization.
Patients received either NUCALA 100 mg administered subcutaneously (SC), mepolizumab 75 mg administered intravenously (IV), or placebo treatment once every 4 weeks over 32 weeks. The primary endpoint, reduction in the frequency of clinically significant exacerbations of asthma was statistically significant (p<0.001). Table 1, provides the results of the primary endpoint and secondary endpoints of MEA115588. (See Table 1.)
Click on icon to see table/diagram/imageOral Corticosteroid Reduction MEA115575 (SIRIUS) Study: MEA115575 evaluated the effect of NUCALA 100 mg SC on reducing the use of maintenance oral corticosteroids (OCS) while maintaining asthma control in subjects with severe eosinophilic asthma who were dependent on systemic corticosteroids.
Patients had a peripheral blood eosinophil count of ≥300/μL in the 12 months prior screening or a peripheral blood eosinophil count of ≥150/μL at baseline. Patients were administered NUCALA or placebo treatment once every 4 weeks over the treatment period. The OCS dose was reduced every 4 weeks during the OCS reduction phase (Weeks 4-20), as long as asthma control was maintained. During the study patients continued their baseline asthma therapy [i.e., high-dose inhaled corticosteroids (ICS) in combination with at least another controller such as long-acting beta2-adrenergic agonists (LABA) or leukotriene modifiers].
This study enrolled a total of 135 patients: mean age of 50 years, 55% were female, 48% had been receiving oral steroid therapy for at least 5 years, and had a baseline mean prednisone equivalent dose of approximately 13 mg per day.
The primary endpoint was the reduction in daily OCS dose (weeks 20-24) whilst maintaining asthma control compared with patients treated with placebo (see Table 2).
Click on icon to see table/diagram/imageAdditionally, health-related quality of life was measured using SGRQ. At Week 24, there was a statistically significant improvement in the mean SGRQ score for NUCALA compared with placebo: -5.8 (95% CI: -10.6, -1.0; P=0.019). At Week 24, the proportion of subjects with a clinically meaningful decrease in SGRQ score (defined as a decrease of at least 4 units from baseline) was greater for NUCALA (58%, 40/69) compared with placebo (41%, 27/66).
The long-term efficacy profile of NUCALA in severe 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.
Open Label Extension Study MEA115661 (COSMOS) Study: Following completion of the double-blind MEA115575 and MEA115588 studies, all patients were offered the opportunity to participate in MEA115661, a 52-week open-label extension (OLE) study, during which time all patients received open-label mepolizumab (100 mg SC). In total, 651 patients (126 subjects who had previously participated in study MEA115575 and 525 subjects who had previously participated in Study MEA115588), received 100 mg SC of mepolizumab every 4 weeks. During open-label treatment of all subjects with mepolizumab in MEA115661, the rates of exacerbations per year remained low in the subjects who were previously treated with mepolizumab and were consistent with results demonstrated during the 32-week double-blind period of study MEA115588. In addition, the impact of mepolizumab on steroid reduction was maintained following MEA115575 with average daily steroid dose remaining consistent with the level achieved with mepolizumab treatment at Weeks 20-24 during MEA115575.
Pharmacokinetics: Following subcutaneous dosing in subjects with moderate/severe asthma, mepolizumab exhibited approximately dose-proportional pharmacokinetics over a dose range of 12.5 mg to 250 mg.
Absorption: 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.
Distribution: Following a single intravenous administration of mepolizumab to patients with asthma, the mean volume of distribution is 55 to 85 mL/kg.
Metabolism: Mepolizumab is a humanized IgG1 monoclonal antibody degraded by proteolytic enzymes which are widely distributed in the body and not restricted to hepatic tissue.
Elimination: 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.
Special Patient Populations: The population pharmacokinetics of mepolizumab were analyzed to evaluate the effects of demographic characteristics. Analyses of these limited data suggest that no dose adjustments are necessary for race or gender.
Elderly patients (> 65 years old): No formal studies have been conducted in elderly patients. However, in the population pharmacokinetic analysis, there was no indication of an effect of age (12-82 years of age) on the pharmacokinetics of mepolizumab.
Renal impairment: 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.
Hepatic impairment: 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.
Toxicology: Pre-clinical Safety Data: Carcinogenesis/mutagenesis: As mepolizumab is a monoclonal antibody, no genotoxicity or carcinogenicity studies have been conducted.
Reproductive Toxicology: Fertility: 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 F1 assessment.
Pregnancy: 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 crosses the placenta. Concentrations of mepolizumab were approximately 2.4 times higher in infants than in mothers for several months post-partum and did not affect the immune system of the infants.
Animal toxicology and pharmacology: 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 have been 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.
